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TABLE 1: Major Experimental Models of Aggression in Laboratory Animals
Model and Species | Procedure | Behavioral Topography | Biological Function |
A. Aversive environmental manipulations |
|
|
|
Isolation-induced aggression, mostly in mice | Isolated housing before confrontation with another isolate or group-housed animal | Complete agonistic behavior pattern: isolates attack, threaten, pursue opponent | Territorial defense or compulsive, abnormal, pathological behavior |
Pain-elicited or shock-induced aggression, mostly in rats, also in monkeys | Pairs of animals are exposed to pulses of electric shock delivered through grid floor or to the tail | Defensive reactions, including upright postures, bites toward face of opponent, audible vocalizations; bites toward inanimate targets | Some similarity to reaction toward predator or toward large opponent |
Aggression due to omission of reward, mostly in pigeons, also in monkeys | Conditioning history; schedule-controlled operant behavior; omitted or infrequent reinforcement | Attack bites or pecks, threat displays towards suitable object or conspecific | Competition for resources such as food, sex, protected niches (?) |
B. Brain manipulations |
|
|
|
Brain lesion-induced aggression, mostly in rats, also in cats | Destruction of neural tissue, and subsequent social or environmental challenges | Defensive reactions, biting | Neurological disease |
Brain stimulation-induced aggression, mostly in cats, also in rats | Electrical excitation of tissue in diencephalon and mesencephalon, also in other limbic or cerebellar areas | (1) Defensive reactions accompanied by autonomic arousal | Defense against attacker |
|
| (2) Predatory attack and killing | Predation |
C. Ethological situations |
|
|
|
Aggression by resident toward intruder, in most species and in both sexes | Confrontation with an unfamiliar adult member of the species | Full repertoire of agonistic behavior (attack and threat vs. defense, submission, and flight) | Territorial or group defense (?); rivalry among males and among females |
Female aggression, mostly in maternal rodents | Lactating female, in the presence of litter, confronting an intruder male | Species-specific repertoire of attack and threat behavior toward intruder | Defense of young, competition for resources and territory |
Dominance-related aggression, mostly in monkeys, mice, and rats | Formation or maintenance of a social group | Species-specific repertoire of signals (displays, sounds, odors) between group members of different social rank; low level and intensity of agonism | Social cohesion and dispersion |
D. Killing |
|
|
|
Muricide, mostly in rats, cats | Presence of prey, food deprivation | Stalking, seizing, killing, sometimes consuming prey | Food source; ''killer instinct" |
Source: Adapted from Miczek and DeBold (1983). | |||
TABLE 2: Catecholamines
References | Methods and Procedures | Results and Conclusions |
A. Noradrenergic Correlates of Animal Aggression |
| |
Whole brain measurements |
|
|
Isolation-induced Aggression |
|
|
Welch and Welch 1965 | Comparison of isolated and group-housed male mice. No aggression measured | Isolated mice had higher whole brain levels of NE (mg/g) than group-housed mice. |
Welch and Welch 1968a, 1970 | Male mice grouped in a neutral environment for varying lengths of time (10 mins-2.5 hrs). Animals were sacrificed immediately after the aggressive interaction. Whole brain NE (ng/g) and DA were assayed. | The earlier study reported no difference in NE levels as a function of aggressive experience, while the later study reported decreases (8%) in NE following a 30 min fight. |
Modigh 1974 | Male mice placed together in a neutral environment for 30 min. Animals were sacrificed immediately after the aggressive interaction. AMPT or NSD 1015 (aromatic amino acid decarboxylase inhibitor) was used to estimate turnover in whole brain. | Fight experience resulted in increased AMPT or NSD 1015-induced depletion of NE (µg/g). |
Hutchins et al. 1974, 1975 | Male mice placed together in a neutral environment. Animals were sacrificed immediately after the behavioral interaction. HVA and DOPAC were assayed in the striatum. | DOPAC levels (µg/g) in the striatum were higher in isolated mice transferred to a new environment for 15 min, with or without an agonistic interaction, in comparison to isolated mice left undisturbed. DOPAC levels in group-housed mice were not altered when they were placed in a new cage. Striatal concentrations of DA was not affected by housing or transfer. |
Bernard et al. 1975 | Male mice tested in a neutral environment against a similarly treated conspecific. Strain (BALB, ICR and C57B1/6J), housing, (group or isolated) and age (isolated 6 or 30 weeks) were varied. Catecholamine dynamics in whole brain were measured 24 hrs after agonistic interaction. Turnover was estimated with AMPT. | C57B1/6J did not fight and had higher NE (ng/g) levels than the other strains. Age or strain related differences in NE rate and utility constants did not vary as a function of aggressivity. Differential housing did not alter any of the biochemical measures. |
Karczmar et al. 1973; Goldberg et al. 1973 | Comparison of neurochemistry in different strains of male mice; turnover was estimated using AMPT. | Neural levels or turnover rates of NE (µg/g) are not correlated with aggression levels across strains. |
Dominance-related Aggression |
|
|
McIntyre et al. 1979 | Comparison of whole brain NE in dominant and submissive rainbow trout. | Submissive fish that are rarely attacked have comparable NE to dominant fish. Submissive fish that are attacked have increased NE compared to dominant fish |
McIntyre and Chew 1983 | Comparison of whole brain NE in dominant and submissive pheasants. | Dominance status was not correlated with catecholamine concentrations (ng/g). |
Hadfield and Weber 1975 | Pairs of group-housed mice were tested in a neutral arena. NE uptake was measured in whole brain synaptosomes immediately following the agonistic interaction | Fighting increases Km and Vmax for NE uptake compared to non-fighting controls. |
Regional brain measurements |
|
|
Isolation-induced Aggression |
|
|
Welch and Welch 1969b | Male mice grouped in a neutral environment for varying lengths of time (5, 45, 60, 150 mins). Animals were sacrificed immediately after the aggressive interaction. NE (ng/g) was assayed in the metencephalon, mesencephalon and telencephalon. | Fighting experience was associated with decreased NE in the brain stem at all time points. NE was elevated in the telencephalon after a 150 min interaction. |
Modigh 1973 | Male mice placed together in a neutral environment for 30 min. Animals were sacrificed immediately after the aggressive interaction. NE and its precursors and metabolites were assayed in the striatum, cerebral hemispheres and the rest of the brain. NSD 1015 (aromatic amino acid decarboxylase inhibitor) was used to estimate turnover | In animals administered NSD 1015, fight experience resulted in decreased NE, and increased tyrosine, and DOPA accumulation in each brain region, compared to isolates with no fight experience. Whole brain concentrations of HVA were also lower following attack experience. |
References | Methods and Procedures | Results and Conclusions |
Hutchins et al. 1974, 1975 | Male mice placed together in a neutral environment. Animals were sacrificed immediately after the behavioral interaction. HVA and DOPAC were assayed in the striatum. | DOPAC levels (µg/g) in the striatum were higher in isolated mice transferred to a new environment for 15 min, with or without an agonistic interaction, in comparison to isolated mice left undisturbed. DOPAC levels in group-housed mice were not altered when they were placed in a new cage. Striatal concentrations of HVA or NE were not affected by housing or transfer. |
Tizabi et al. 1979 | Comparison of neurochemistry and aggression in 3 strains of male mice. NE was assayed in 14 brain regions. Turnover was estimated using AMPT. | The most aggressive strain had higher steady state levels and turnover rate of NE in the frontal cortex, caudate nucleus and hypothalamus compared to the least aggressive strain. |
Tizabi et al. 1980 | Male mice placed together in a neutral arena were sacrificed 48 hrs after the last behavioral interaction. NE was assayed in 17 nuclei. AMPT was used to estimate turnover. | Mice that attacked had higher levels of NE (pg/υg) in the septum and lower levels in the olfactory tubercle and substantia nigra than mice that did not attack. Aggressive mice had increased NE turnover in the A10 region. |
Hadfield and Milio 1988 | Pairs of male mice tested in a neutral arena. Animals were sacrificed immediately after behavioral interactions. NE and its metabolites were assayed in 10 brain regions. | MHPG/NE levels were not significantly altered as a function of fighting experience. |
Thoa et al. 1977 | Comparison of neurochemistry in isolated and group-housed male rats. Rats were isolated for 13 weeks. NE was estimated in 23 nuclei using AMPT. | Following isolation, steady state NE (ng/mg protein) was decreased in the hippocampus and n. amygdala centralis and increased in the entorhinal cortex compared to group-housed controls. NE turnover was decreased in the cingulate cortex, caudate nucleus, stria terminalis and paraventricular nucleus. |
Pain-induced Aggression and Defense |
|
|
Stolk et al. 1974 | Electric foot shock aggression in male rats. Animals were sacrificed immediately after the aggressive interaction. NE was assayed in the brain stem, diencephalon and telencephalon | Rats that were shocked but not given the opportunity to fight with another animal had decreased NE (µg/g) and increased normetanephrine in the brain stem; in rats that fought, brainstem concentrations of NE and metabolites were comparable to controls. |
Tsuda et al. 1988 | Restraint stress-induced target biting in male rats. Animals were sacrificed immediately or 50 min after restraint. Plasma corticosterone was measured. NE and MHPG were assayed in 8 brain regions | 50 min after restraint, rats given the opportunity to bite had lower plasma corticosterone (mg/dl) and lower MHPG in the hypothalamus, amygdala, thalamus, and basal ganglia than rats not given the opportunity to bite. |
Brain lesion-induced Aggression |
|
|
Reis and Fuxe 1964; 1968 | "Sham rage" in cats following acute brainstem transection. NE histofluorescence was measured in the hindbrain. H 44/68 was used to estimate NE turnover. | Decerebration above the superior colliculus was associated with both "sham rage" and increased NE turnover. Midcollicular transected cats, which did not manifest "sham rage" had comparable NE turnover to controls. Haloperidol blocked this effect. |
Salama and Goldberg 1973a | Comparison of neurochemistry in septal-lesioned and sham-lesioned male rats. NE was measured in the forebrain and hindbrain. Turnover was estimated using AMPT | Septal-lesioned rats had increases in steady-state NE (µg/g) and NE turnover rate (µg/g/hr) in the hindbrain compared to controls |
Defensive Aggression induced by brain stimulation |
|
|
Reis and Gunne 1965 | "Sham rage" following electrical stimulation of the amygdala in male and female cats. Animals were sacrificed immediately after the behavioral interaction. NE was measured in the brainstem, telencephalon and adrenal gland. | Animals that became defensive had decreased NE (ng/g) in the brain and decreased NE in the adrenal compared to non-stimulated controls or animals that did not become defensive upon amygdala stimulation. |
Aggression by Resident toward an Intruder |
|
|
Payne et al. 1984, 1985 | Isolated and group-housed male hamsters sacrificed after the behavioral interaction. NE was assayed in the midbrain and hypothalamus. | More aggressive isolates do not differ from less aggressive group-housed hamsters in NE levels (ng/100 mg) in the hypothalamus and midbrain. Attack experience did not alter the percentage change in NE following pargyline or AMPT, respectively. Residents defeated by intruders had amine changes similar to attackers. |
References | Methods and Procedures | Results and Conclusions |
Killing |
|
|
Goldberg and Salama 1969 | Muricide by male rats. Forebrain and hindbrain NE was measured 24 hrs following muricide. AMPT was used to estimate turnover | Muricidal rats had increased NE (µg/g) in the forebrain compared to non-muricidal rats. The effects of AMPT were similar in muricidal and non-muricidal groups. |
Barr et al. 1979 | Muricide by isolated male rats. Animals were sacrificed 1 week after attack experience. NE was assayed in the hypothalamus, amygdala and olfactory bulbs | Concentrations of NE (ng/mg protein) were similar in muricidal and non-muridical rats in all 3 brain regions |
Salama and Goldberg 1973b | Muricide by male rats. Forebrain NE and turnover were measured at 2, 24, 48 hrs or 1 week following muricide; Radioactively labelled NE was used to estimate turnover | Forebrain NE levels (µg/g) and turnover rate were elevated 2 or 24 hrs after muricide, but not 48 hrs or 1 week later. |
Tani et al. 1987 | Muricide by male rats with olfactory bulbectomy or n. raphe or n. accumbens lesioning. Animals were sacrificed immediately after muricide. NE and its metabolites were assayed in the frontal cortex and hypothalamic and amygdaloid nuclei. | Muricidal rats had increased NE (ng/mg protein) in the hypothalamus and increased HVA and DOPAC in the frontal cortex and LH in comparison to intact non-muricidal rats. Type of lesion did not affect neurochemical measures. |
B. Dopaminergic Correlates of Animal Aggression |
| |
Whole brain measurements |
|
|
Isolation-induced Aggression |
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|
Welch and Welch 1968b, 1970 | Male mice grouped in a neutral environment for varying lengths of time (10 mins–2.5 hrs). Animals were sacrificed immediately after the aggressive interaction. | DA levels (ng/g) were not altered as a function of aggressive experience. |
Modigh 1974 | Male mice placed together in a neutral environment for 30 min. Animals were sacrificed immediately after the aggressive interaction. AMPT or NSD 1015 (aromatic amino acid decarboxylase inhibitor) was used to estimate turnover in whole brain. | Fight experience resulted in increased AMPT but not NSD 1015-induced depletion of DA (µg/g). |
Bernard et al. 1975 | Male mice tested in a neutral environment against a similarly treated conspecific. Strain (BALB, ICR and C57B1/6J), housing, (group or isolated) and age (isolated 6 or 30 weeks) were varied. Catecholamine dynamics in whole brain were measured 24 hrs after agonistic interaction. Turnover was estimated with AMPT. | BALB mice fought at 6 and 30 weeks of isolation and had higher DA levels than the other strains at either time point. Age or strain related differences in DA rate and utility constants did not vary as a function of aggressivity. Differential housing did not alter any of the biochemical measures. |
Karczmar et al. 1973; Goldberg et al. 1973 | Comparison of neurochemistry in different strains of male mice; turnover was estimated using AMPT. | Neural levels or turnover rates of DA (µg/g) are not correlated with aggression levels across strains. |
Lasley and Thurmond 1985 | Compared NE, DA, 5HT and major metabolites in isolated and group-housed mice confronting a male conspecific in a neutral arena; not clear when amines were measured in relation to the agonisitic experience. | Mice that were isolated for 5 days were more aggressive and had higher DOPAC and HVA levels (µg/g) than group-housed mice. After 14 days of isolation, frequency of attack was comparable in isolated and group-housed mice, but the isolated group had elevated DA turnover (HVA:DA). |
Pain-induced Aggression and Defense |
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Anand et al. 1985 | Electric foot shock in female rats with substantia nigra, septal, or amygdala lesions. Timing of neurochemical measures in relation to behavior not specified | Aggression frequency was increased by substantia nigra or septum lesions and decreased by amygdala lesions. DA (µg/g) was only decreased in the septal-lesion group. |
Dominance-related Aggression |
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McIntyre et al. 1979 | Comparison of whole brain DA in dominant and submissive rainbow trout. | Submissive fish that are rarely attacked have DA levels comparable to dominant fish. Submissive fish that are attacked have decreased DA compared to dominant fish |
McIntyre and Chew 1983 | Comparison of whole brain DA in dominant and submissive pheasants. | Dominance status was not correlated with altered catecholamine concentrations (ng/g). Lower rank in the social hierarchy was associated with decreased DA in the neostriatum |
References | Methods and Procedures | Results and Conclusions |
Regional brain measurements |
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Isolation-induced Aggression |
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Welch and Welch 1969b | Male mice grouped in a neutral environment for varying lengths of time (5, 45, 60, 150 mins). Animals were sacrificed immediately after the aggressive interaction. DA was assayed in the metencephalon, mesencephalon and telencephalon. | Fighting experience was associated with decreased DA in the brain stem. DA was elevated in the telencephalon after a 150 min interaction. |
Modigh 1973 | Male mice placed together in a neutral environment for 30 min. Animals were sacrificed immediately after the aggressive interaction. DA and its precursors and metabolites were assayed in the striatum, cerebral hemispheres and the rest of the brain. NSD 1015 (aromatic amino acid decarboxylase inhibitor) was used to estimate turnover. | In animals administered NSD 1015, fight experience resulted in increased tyrosine and DOPA accumulation in each brain region compared to isolates with no fight experience. Whole brain concentrations of HVA were also lower following attack experience. |
Hutchins et al. 1974, 1975 | Male mice placed together in a neutral environment. Animals were sacrificed immediately after the behavioral interaction. HVA and DOPAC were assayed in the striatum. | DOPAC levels (µg/g) in the striatum were higher in isolated mice transferred to a new environment for 15 min, with or without an agonistic interaction, in comparison to isolated mice left undisturbed. DOPAC levels in group-housed mice were not altered when they were placed in a new cage. Striatal concentrations of DA were not affected by housing or transfer. |
Tizabi et al. 1979 | Comparison of neurochemistry and aggression in 3 strains of male mice. DA was assayed in 14 brain regions. Turnover was estimated using AMPT | The most aggressive strain had higher steady state levels and turnover rate of DA in the frontal cortex, caudate nucleus and hypothalamus compared to the least aggressive strain. |
Tizabi et al. 1980 | Male mice placed together in a neutral arena were sacrificed 48 hrs after the last behavioral interaction. DA was assayed in 17 nuclei. AMPT was used to estimate turnover. | DA levels in aggressive mice were lower in the olfactory tubercle and higher in the caudate putamen. Aggressive mice had decreased DA turnover in the olfactory tubercle and caudate-putamen. |
Hadfield 1981, 1983 | Groups of male mice tested in a neutral arena. Animals were sacrificed immediately after the behavioral interaction. DA uptake was measured in the prefrontal cortex and caudate-putamen. | Fighting increased DA uptake (Km and Vmax) in the prefrontal cortex but not in the caudate-putamen. |
Hadfield and Milio 1988 | Pairs of male mice tested in a neutral arena. Animals were sacrificed immediately after behavioral interactions. DA and its metabolites were assayed in 10 brain regions. | There was an overall increase in DOPAC:DA ratios following fighting; changes in DA utilization within individual tissues were not significant. |
Thoa et al. 1977 | Comparison of neurochemistry in isolated and group-housed male rats. Rats were isolated for 13 weeks. DA turnover was estimated in 23 nuclei using AMPT | Steady state DA was decreased in the n. amygdala centralis and increased in the olfactory tubercle of isolated rats. DA turnover was also decreased in the n. amygdala centralis. |
Aggression by Resident toward an Intruder |
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Barr et al. 1979 | Isolated male rats were sacrificed 1 week after agonistic experience. DA was assayed in the hypothalamus, amygdala and olfactory bulbs. | Rats that attacked an intruder hypothalamic DA (ng/mg protein) compared to rats that did not attack. |
Haney et al. 1990 | Pair-housed male mice. DA measurements in the n.accumbens, corpus striatum and amygdala were obtained following 0, 1 or 10 daily attack experience | DOPAC:DA in the n. accumbens was increased following 1 attack experience. Amine measurements in mice with repeated attack experience did not differ from behaviorally naive controls. |
Killing |
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Barr et al. 1979 | Muricide by isolated male rats. Animals were sacrificed 1 week after attack experience. DA was assayed in the hypothalamus, amygdala and olfactory bulbs. | Concentrations of DA (ng/mg protein) were similar in muricidal and non-muricidal rats in each brain region |
Broderick et al. 1985 | Muricide by male rats. Animals were sacrificed 1–2 hrs following the introduction of the mouse into the home cage. DA and its metabolites were assayed in the hypothalamus, thalamus, hippocampus, striatum, cortex and brain stem | Muricidal rats had increased DOPAC in the septum and DA in the anterior hippocampus compared to non-muricidal rats. |
References | Methods and Procedures | Results and Conclusions |
Tani et al. 1987 | Muricide by male rats with olfactory bulbectomy, n.raphe or n.accumbens lesioning. Animals were sacrificed immediately after muricide. DA and its metabolites were assayed in the frontal cortex and hypothalamic and amygdaloid nuclei | Muricidal rats had increased HVA and DOPAC in the frontal cortex and LH in comparison to intact non-muricidal rats. Type of lesion did not affect neurochemical measures. |
C. Catecholaminergic Correlates of Human Aggression and Violence |
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CSF Correlates of Human Aggression |
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Inpatient studies |
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Subrahmanyam 1975 | Schizophrenic, manic-depressive psychotics and healthy controls were compared: 6/60 acute schizophrenics were in an ''acute aggressive state". CSF MHPG and HVA and urinary NE, EPI, 5HIAA, MHPG and VMA were measured | CSF MHPG (ng/ml) in acute, aggressive schizophrenics was comparable to controls but higher than non-aggressive acute schizophrenics. Urinary amines appeared elevated in aggressive schizophrenics in comparison to both controls and non-aggressive schizophrenics. No statistics reported |
Brown et al. 1979 | CSF MHPG was measured in military men diagnosed with borderline personality disorder without affective illness (n=26). | CSF MHPG (ng/ml) did not differ in patients with borderline personality disorder and normal controls. If just the patients are analyzed, there is a positive correlation between scores based on the life history of aggression and CSF MHPG. |
Criminal Violence |
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Bioulac et al. 1980 | CSF DA was measured in healthy controls (n=5) and XYY patients arrested for crimes ranging from vagrancy to assault (n=6). Probenicid was used to estimate turnover | DA levels and turnover did not differ between groups. No statistics were reported |
Linnoila et al. 1983 | CSF NE, MHPG, DOPAC, and HVA were assayed in men convicted of violent crime. Subjects were subdivided into categories specifying the pre-meditated or impulsive nature of the criminal act. | Catecholamine levels or turnover rates did not differ between groups. |
Peripheral Correlates of Human Aggression |
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Outpatient Studies |
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Perini et al. 1986 | Plasma NE and EPI in 24 borderline hypertension patients and 24 controls given psychological tests to assess suppressed aggression and anxiety. | Compared to subjects without suppressed aggression, borderline hypertensives with suppressed aggression had higher heart rates, diastolic blood pressures and plasma NE following one of the two mildly stressful conditions (mental arithmetic and the Stroop reading task). |
Experimental Studies |
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Ekkers 1975 | Urinary methyladrenaline, methylnoradrenaline, VMH and creatinine were measured in 12–17 year old males. Subjects participated in 3 laboratory measures of aggression involving the administration of aversive noise to another person. | The reliability of the aggression measures was low. Methyladrenaline weakly correlated with aggression (no units). |
Criminal Studies |
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Wiedeking et al. 1977 | Plasma NE and DBH in an XYY and an XXY male (n=2) convicted of murder and rape were compared to "normal" males (n=9) under resting conditions and during physical and emotional stress. | Levels of plasma Ne and DBH (pg/ml) did not differ between violent and non-violent subjects. |
Woodman et al. 1977 | Urinary and plasma EPI and NE were measured in incarcerated male patients in a maximum security hospital setting. Half the men were convicted of violent personal attack and half were convicted of arson, sexual or property offenses (n=50). | Men convicted of violent personal attack, other than rape, had had lower plasma and urinary EPI and higher urinary NE than men convicted of other types of offenses. |
Sandler et al. 1978 | Comparison of violent and non-violent prisoners (n=10). | Plasma concentrations of free and conjugated phenylacetic acid (metabolite of phenylethylamine) were elevated in violent prisoners. |
References | Methods and Procedures | Results and Conclusions |
Woodman and Hinton 1978a, b; Woodman 1979 | Urinary cAMP, NE, and EPI (control for differences due to urine volume) were measured in incarcerated male patients in a maximum security hospital setting. Criminal convictions were of a wide variety. Healthy men and mentally ill patients without a history of violence served as controls. Subjects were exposed to "stressful" experimental procedures. | EPI (nmol/g creatinine) was elevated in both incarcerated and mentally ill men; NE was elevated in the mentally ill group. The incarcerated offenders were subdivided into two groups based on their anticipatory response to an upcoming stressful event: Group 1 was similar to controls. Group 2 had less cortisol and EPI and more NE in their urine than the other groups. Group 2 was categorized, post hoc, as more violent. Differential response to stress in Group 2 patients was replicated 4–25 months later. |
Boulton et al. 1983 | Plasma phenylacetic acid, m-hydroxyphenylacetic acid, p-hydroxyphenylacetic acid and platelet MAO were measured in non-violent male offenders, healthy controls, and violent offenders (murder, rape, physical assault) that were undergoing neuroleptic drug treatment (n=23). | Violent offenders had lower unconjugated p-hydroxyphenylacetic acid (ng/ml) and conjugated phenylacetic acid than non-violent offenders (p < .10); platelet MAO did not differ between groups. |
D. Neuropharmacological Manipulations of Catecholamines |
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Animal Studies |
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Catecholamine synthesis manipulation |
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Isolation-induced Aggression |
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Kletzkin 1969; Rolinski 1973; Hodge and Butcher 1975; Herbut and Rolinski 1985; Rolinski and Herbut 1985 | Similarly-treated pairs of male mice tested in a neutral arena | L-DOPA (200–800 mg/kg i.p.) and DL-DOPA (250, 500 mg/kg i.v) decreased attack frequency at doses that often increased stereotypies; whole brain DA (mg/g) was increased and n. accumbens 5-HT was decreased. L-DOPA (50 mg/kg) co-adminstered with nialamide (40 mg/kg i.p.) increased aggression compared to non-injected controls. |
Miczek 1977; Miczek and O'Donnell 1978 | Male rats confronting a male conspecific | L-DOPA (10 mg/kg i.p.) increased attack frequency; higher doses (20, 200 mg/kg i.p.) decreased attack frequency. |
Pain-induced Aggression and Defense |
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Torda 1976 | Electric foots shock in pairs of similarly treated male rats | AMPT (20–50 µg) infused into the VMH decreased aggression. |
Drug-Induced Aggression |
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Vander Wande and Spoerlein 1962; Bryson and Bischoff 1971 | DOPA-induced target biting in group-housed male mice | DOPA (400–500 mg/kg i.v.) induced catatonia, stupor and biting of inanimate objects placed near the mouth. Biting induced by L-DOPA (500–970 mg/kg i.p.) was associated with hyperactivity and jumping. |
Troncone et al. 1988 | Apomorphine-induced aggression in REM sleep-deprived male rats. Both members of the pair were similarly treated. | L-DOPA (200 mg/kg i.p.) reduced aggression. |
Defensive Aggression induced by brain stimulation |
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Katz and Thomas 1976 | Quiet predatory aggression induced by LH stimulation | AMPT (70 mg/kg i.p.) raised the threshold of stimulation necessary to elicit attack and decreased approach and biting of attack object. |
Aggression by Resident toward Intruder |
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Thurmond et al. 1977, 1979, 1980 | Male group-housed male mice isolated overnight confronted a naive intruder. Diets were supplemented with amino acid precursors. | Aggression and locomotion were enhanced when l-tyrosine (2,4%) and l-phenylalanine (2,4%), were administered alone or in combination for 1–2 weeks. Tyrosine increased whole brain levels of tyrosine, 5-HT and 5HIAA. Phenylalanine treatment increased phenylalanine and tyrosine levels. After 5 weeks of dietary supplement, tolerance developed to the enhancement in aggression but not to the neurochemical alterations. |
Diringer et al., 1982 | Male mice were fed isocaloric diets with supplemental casein or tyrosine. | High doses (50–60 mg/kg i.p.) of the DBH inhibitor fusaric acid inhibited aggression. These doses reduced brain NE and DA but increased 5-HT and 5HIAA. |
Miczek and O'Donnell 1978 | Male rats housed with a female confronted a male conspecific | L-DOPA (100–200 mg/kg i.p.) following carbidopa pretreatment decreased attack frequency. |
References | Methods and Procedures | Results and Conclusions |
Dominance-related Aggression |
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Benkert et al. 1973 | Group-housed male rats | Pretreatment with reserpine (2 mg/kg i.p.) 16 hours before the combined administration of the dopa decarboxylase inhibitor, Ro 4-4602 (50 mg/kg i.p.) and L-DOPA (200 mg/kg i.p.) increased fighting. |
Redmond et al. 1971a, b. | Group-housed male and female macaques. | AMPT (160–250 mg/kg p.o, twice daily/14 days) decreased attacks, threats and social rank in 50% of animals. Facial expressions and motor activity were also suppressed. Urinary MHPG and VMA were significantly decreased. |
Killing |
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Banerjee 1974; McLain et al. 1974 | Individually housed male rats | AMPT (3x 125 mg/kg i.p.) decreased muricide and produced marked sedation; AMPT (50 mg/kg i.p. 3x daily for 3 days) increased muricide. |
Schmidt 1979, 1983 | Predatory aggression in ferrets | L-DOPA (30, 60 mg/kg p.o.) disrupted capture, pursuit and biting of prey. |
Catecholamine Agonists |
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Experimenter-elicited Aggression |
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Maler and Ellis 1987 | High frequency electric organ discharges in South American electric fish elicited by simulated electric signals. | NE (.1 µg i.c.v.) increased aggressive signalling |
Isolation-induced Aggression |
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Hodge and Butcher 1975; Lassen 1978 | Pairs of similarly treated male mice placed together in a neutral arena | Apomorphine (200–800 mg/kg i.p.) decreased attack frequency at doses that increased stereotypies. Clonidine (0.05–.15 mg/kg) and piperoxan (10,20 mg/kg) also inhibited aggression. An ineffective dose of piperoxan (5 mg/kg) reduced the antiaggressive effect of clonidine. |
Puech et al. 1974; Thor and Ghiselli 1975 | Groups of male rats placed together in a neutral arena | Apomorphine (0.125–8.0 mg/kg i.v. or 20 mg/kg i.p.) decreased locomotion and increased aggression. |
Baggio and Ferrari 1980 | Male mice confronted an untreated male intruder within the home cage isolated 20 days | DA agonists, apomorphine (0.05–5 mg/kg i.p.) and dose-dependently reduced aggression. These effects were reversible with haloperidol. Locomotion not reported. |
Pain-induced Aggression and Defense |
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Geyer and Segal 1974; Torda 1976; Baggio and Ferrari 1980; Ray et al. 1983 | Electric foots shock in pairs of similarly treated male rats | Aggression was increased by intraventricular administration of DA (1, 3, 6, 50 µg/µl) and decreased by NE (.5, 2, 50 µg/µl i.c.v.); pain sensitivity was not altered. The combined microinjection of NE and DA (10–50 ng/2 ml) into the VMH increased aggression. Both apomorphine (0.05–5 mg/kg i.p.) and N-n-propylnorapomorphine (1–100 mg/kg i.p.) also increased aggression. These effects were reversible with haloperidol. |
Drug-induced aggression |
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Maj et al. 1987 | Clonidine-induced aggression in groups of male mice | Beta antagonist, adimolol (10 mg/kg) reduced aggression. |
Hasselager et al. 1972 | d-Amphetamine-induced aggression in groups of male mice | AMPT (350 mg/kg s.c.) decreased aggression, which is defined as abrupt locomotion, defensive posture and sound. |
Troncone et al. 1988 | Apomorphine-induced aggression in REM sleep-derived male rats. Both members of the pair were similarly treated. | Bromocriptine (no dose reported) did not affect aggression |
Nagy and Decsi 1974; | Intrahypothalamic carbachol-induced "sham rage" in male and female cats | NE (20–50 µg) or isoprenaline (50 µg) administered into the dorsal hippocampus reversed the effects of carbachol. Intrahippocampal DA (50 µg) or phenylephrine (50 µg) did not |
References | Methods and Procedures | Results and Conclusions |
Defensive Aggression induced by brain stimulation |
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Torda 1976 | "Sham rage" elicited by electrical stimulation of the hypothalamus in male rats | Frequency of aggression was increased by NE and DA and decreased by phentolamine, propranolol and AMPT infused into the ventromedial hypothalamus. Threshold to elicit aggression was also changed. |
Barrett et al. 1987, 1990 | "Sham rage" and quiet biting elicited by electrical stimulation of the hypothalamus in male and female cats | Injections of NE (250–500 ng) or clonidine (.9 nmol) into the anterior hypothalamus reduced the threshold for hissing; yohimbine (775 ng) blocked the NE facilitation. |
Goldstein and Siegel 1980 Crescimanno et al. 1986; Maeda and Maki 1986; | "Sham rage" and quiet biting elicited by electrical stimulation of the hypothalamus in male and female cats | Substantia nigra stimulation reduced the threshold and the latency to hiss. In contrast, ventral tegmental and n. accumbens stimulation suppressed sham rage and quiet biting. Apomorphine (1 mg/kg) reversed the inhibitory effect of amygdaloid lesions on attack induced by hypothalamic stimulation. |
Aggression by Resident toward Intruder |
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Winslow and Miczek 1983; Tidey and Miczek 1991 | Male pair-housed mice encountering a male conspecific | Apomorphine (.1–1.0 mg/kg i.p.) decreased attacks, aggressive threats and locomotor activity. Specific D1 (SKF 38393 3–100 mg/kg i.p.) and D2 (quinpirol .1–1.0 mg/kg i.p.) agonists also decreased aggressive behavior. |
Dominance-related Aggression |
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McKenzie 1971 | Pairs of male or female group-housed rats | Apomorphine (10–30 mg/kg i.p.) increased aggression between males if at least one member of the pair was dominant within its group. Apormorphine did not enhance aggression in females. |
Killing |
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Rolinski 1975; Baggio and Ferrari 1980; Shibata et al. 1982; Berzsenyi et al. 1983; Pucilowski and Valzelli 1986; Molina et al. 1987; Isel and Mandel 1989 | Muricide in male and female rats | Killing was inhibited by electrical stimulation of the locus coereleus; inhibition was reversed by clonidine (0.15 mg/kg i.p.). NE (20, 50 µg/2 µl) infusion into the medial amygdala also inhibited muricide; phenoxybenzamine pretreatment (20 mg) reversed this effect. Both apomorphine (0.05–5 mg/kg i.p.) and N-n-propyl-norapomorphine (1–100 mg/kg i.p.) reduced muricide; these effects were reversible with haloperidol. DA (50 µg) infused into the medial amygdala had no effect. |
Baggio and Ferrari 1980 | Predatory aggression by male rats toward turtles | Apomorphine (0.05–5 mg/kg i.p.) and N-n-propyl-norapomorphine (1–100 mg/kg i.p.) reduced muricide; these effects were reversible with haloperidol. |
Bandler 1970, 1971a,b | Ranacide and muricide in male rats | NE (3–10 µg) into the VTA decreased attack latencies in approximately 17% of rats. |
Goldstein and Siegel 1980 | Muricide in non-predatory female cats | Electrical stimulation of VTA or n. accumbens suppressed attack elicited by hypothalamic stimulation without altering the autonomic response. |
Schmidt 1979, 1983 | Predatory aggression in ferrets | Apomorphine (1 mg/kg i.m.) increased the latency to attack. Bromocriptine (8 mg/kg i.m.) decreased the latency to attack and to kill prey. |
Catecholamine Antagonists |
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Killing |
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Hong et al 1987 | Muricide in olfactory bulbectomized male rats | 1 mg/kg of a2 receptor antagonists (e.g. yohimbine) but not a1 antagonist (corynanthine) reduced muricide. |
References | Methods and Procedures | Results and Conclusions |
Catecholamine Lesions |
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Isolation-induced Aggression |
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Yen et al. 1959 | Male albino mice, individually housed for 3 weeks; 5 min. observation | Reserpine (3 mg/kg p.o.) decreased the percentage of mice fighting at doses that decreased activity and jumping. |
Drug-Induced Aggression |
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Senault 1968, 1970, 1971, 1972, 1973, 1974 | Apomorphine-induced aggression in pairs of male rats | Reserpine (5–10 mg/kg i.p.) sensitized non-aggressive rats to the effects of apomorphine. |
Pain-induced Aggression and Defense |
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Chen et al. 1963; Kostowski 1966; Tedeschi et al. 1969 | Electric foot shock in male mice | Peripherally administered reserpine suppressed fighting and motor activity. |
Brunaud and Siou 1959; Eichelman et al. 1972; Thoa et al. 1972a; Eichelman and Thoa 1973; Sorenson and Ellison 1973; Geyer and Segal 1974; Pucilowski and Valzelli 1986 | Electric foot shock in male rats | 6-OHDA (i.c.v. or directly infused into the n. accumbens) increased shock induced fighting without altering jump threshold, motor behavior or spontaneous fighting. Reserpine (.5–5.0 mg/kg, route of administration not specified) had no effect on aggression. |
Drug-induced Aggression |
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Yen et al. 1970 | DL-DOPA-induced target biting in male mice | Reserpine (ED50 1.8 mg/kg i.p.) reversed biting |
McKenzie 1971; Pucilowski et al. 1986, 1987 | Apomorphine-induced aggression in male rats | Reserpine (10 mg/kg i.p.) pretreatment increased sensitivity to apomorphine. Locus coeruleus lesions reduced NE levels, increased striatal 5-HT, and enhanced aggression. Amygdala lesions also reduced NE levels and enhanced aggression; this was reversible with NE infusion into the amygdala. |
Defensive Aggression induced by brain stimulation |
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Nakamura and Thoenen 1972; Dubinsky et al. 1973; Johansson et al. 1974; Beleslin et al. 1986 | "Sham rage" following electrical hypothalamic stimulation in male and female cats. | Low doses of 6-OHDA (2 mg/kg i.c.v.) increased the threshold to induce attack. Higher doses of 6-OHDA (300 µg i.c.v. 2x) increased irritability and defensive biting. The degree of irritability inversely correlated with whole brain NE. Yohimbine, phenoxybenzamine, propranolol, chlorpromazine and haloperidol did not reverse the behavioral effects of 6-OHDA. |
Aggression by Resident toward Intruder |
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Walaszek and Abood 1956 | Male Siamese fighting fish confronting a male conspecific | Reserpine (10 mg/ml) decreased fighting and slightly decreased locomotor activity. |
Dominance-related Aggression |
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Ellison 1976 | Male rats living in colonies with established dominance hierarchies | Individual animals receiving 6-OHDA (25 µg/day i.c.v. for 3 days) became inactive, explored less and decreased in dominance status over a 25 day period. |
Redmond et al. 1973 | Free-ranging colonies of macaques | 6-OHDA (2–30 mg/kg i.c.v. daily/4 days) decreased threat, attack, and other social behaviors; 33% treated individuals failed to return to their colony |
Killing |
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Kostowski 1966 | Predatory aggression in ants towards a beetle | Reserpine (.5 mg/mg p.o.) effects on aggression were time-dependent: fewer ants attacked a beetle 2–3 hrs following drug administration, while a greater percentage attacked 18–24 hours after receiving reserpine. |
Karli 1959; Rolinski 1975; Pucilowski and Valzelli 1986; Molina et al. 1987 | Muricide in male rats | Reserpine (10 mg/kg) or 6-OHDA (2 × 250 mg i.c.v.) increased muricide. 6-OHDA directly administered into the n. accumbens did not increase muricide. |
Banerjee 1974 | Muricide in individually housed male rats | 6-OHDA (2 × 200 µg i.c.v.) increased aggression in rats that were previously indifferent to mice. |
References | Methods and Procedures | Results and Conclusions |
Liou et al. 1985 | Olfactory bulbectomy-induced muricide in male rats | Electroconvulsive shock (ECS) suppressed muricide. 6-OHDA or locus coereleus lesions attenuated these effects but substantia nigra lesions did not. |
Jimerson and Reis 1973 | Ranacide in male rats demonstrating stable attack behavior | Bilateral 6-OHDA (32 µg) administration into the LH decreased the percentage or rats killing frog. Also decreased feeding, drinking and motor activity. L-DOPA (10 mg/kg i.p.) did not restore aggression. |
E. Neuropharmacological Manipulations of Catecholamines |
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Human Studies |
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Inpatient Studies |
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Goodwin et al. 1970 | L-DOPA-induced aggression in hospitalized depressed patients. Clinical state was assessed by nursing staff. Increasing doses of L-DOPA were administered blindly. | Large doses of L-DOPA (over 4 g daily p.o.) failed to alleviate depression and increased verbal and facial expressions of anger in 7 out of 11 patients; physical aggression was not noted. |
Table 3: Serotonin
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
A. 5-HT Correlates of Animal Aggression |
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Whole brain measurements |
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Isolation-induced Aggression |
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Garattini et al. 1967; Valzelli and Garattini 1968 | Comparison of neurochemistry in isolated and group-housed male mice. | Isolated mice had lower whole brain levels of 5HIAA (µg/g) than group-housed mice; 5-HT levels did not differ. Isolation-induced decreases in 5-HT turnover rate did not correlate with the onset of isolation-induced aggression |
Welch and Welch 1968a | Pairs of male mice fought for 60 min and were sacrificed. | Fighting increased whole brain levels of 5-HT (µg/g). PCPA (360 mg/kg i.p.) pretreatment blocked this effect. |
Karczmar et al. 1973; Goldberg et al. 1973 | Comparison of whole brain 5-HT and 5HIAA; turnover was estimated using pargyline in various strains of male mice. | Neural steady state levels or turnover rates are not correlated with aggression levels across strains. |
Lasley and Thurmond 1985 | Compared NE, DA, 5HT and major metabolites in isolated and group-housed mice confronting a male conspecific in a neutral arena; not clear when amines were measured in relation to the agonistic experience. | After 14 days of isolation, isolated and group-housed mice showed comparable levels of aggression but the isolated group had elevated 5HT turnover (5HIAA:5-HT). |
Pain-induced Aggression and Defense |
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Anand et al. 1985 | Electric foot shock in female rats with substantia nigra, septal, or amygdala lesions. Timing of neurochemical measures in relation to behavior not specified | Aggression frequency was increased by substantia nigra or septum lesions and decreased by amygdala lesions. Whole brain measures of 5-HT (mg/g) were decreased in all 3 groups. |
Aggression by Resident toward Intruder |
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Walletschek and Raab 1982 | Individually-housed male tree-shrews encountered male conspecifics | Firing rate of 5-HT-containing neurons in the dorsal raphe decreases during offensive encounters and increases during defensive fighting compared to resting animals. |
Dominance-related Aggression |
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McIntyre et al. 1979 | Comparison of whole brain 5-HT in dominant and submissive rainbow trout. | Submissive fish that are rarely attacked have 5-HT comparable to dominant fish. |
Regional brain measurements |
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Isolation-induced Aggression |
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Modigh 1973 | Male mice placed together in a neutral environment for 30 min. Animals were sacrificed immediately after the aggressive interaction. 5-HT and its precursors and metabolites were assayed in the striatum, cerebral hemispheres and the rest of the brain. NSD 1015 (aromatic amino acid decarboxylase inhibitor) was used to estimate turnover | In animals administered NSD 1015, fight experience resulted in increased tryptophan and 5-HTP accumulation in each brain region, compared to isolates with no fight experience. |
Payne et al. 1984, 1985 | Isolated and group-housed male hamsters sacrificed after the behavioral interaction. 5-HT and 5HIAA were assayed in the midbrain and hypothalamus. | More aggressive isolates do not differ from less aggressive group-housed hamsters in 5-HT and 5HIAA (ng/100 mg) in the hypothalamus and midbrain. Attack experience did not alter the percentage change in 5-HT following pargyline, but confronting an intruder did prevent a pargyline-induced decrease in hypothalamic 5HIAA when measured 20 min post-injection; attack levels did not correlate with changes in 5HIAA. Residents defeated by intruders had amine changes similar to attackers. |
Hadfield and Milio 1988 | Pairs of male mice tested in a neutral arena. Animals were sacrificed immediately after behavioral interactions. 5-HT and its metabolites were assayed in 10 brain regions | 5HIAA:5-HT levels were not significantly altered as a function of fighting experience |
Pain-induced Aggression and Defense |
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Lee et al. 1987 | Electric foot shock in male rats. Animals were sacrificed immediately after aggressive interaction. 5-HT and 5HIAA were measured in the striatum, hippocampus and medial and dorsal raphe nucleus. | Aggressive experience was associated with decreased 5-HT (no units) in the dorsal raphe and striatum and decreased 5HIAA in the hippocampus. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Aggression by Resident toward Intruder |
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Haney et al. 1990 | Pair-housed male mice. 5-HT measurements in the nucleus accumbens, corpus striatum and amygdala were obtained following 0, 1 or 10 daily attack experiences | 5HIAA:5-HT (ng/mg protein) in the amygdala was increased following 1 attack experience. Amine measurements in mice with repeated attack experience did not differ from behaviorally naive controls |
Dominance-related Aggression |
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Garris et al. 1984 | Olfactory-bulbectomized group-housed male mice. Aggression determined by number of head and body lesions | Aggression and 5-HT histofluorescence in the olfactory bulb, lateral olfactory tract and pyriform cortex progressively increased over time since olfactory bulbectomy |
Killing |
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Goldberg and Salama 1969 | Muricide by male rats. Forebrain and hindbrain 5-HT was measured 24 hrs following muricide. | 5-HT levels did not differ between muricidal and non-muricidal rats. |
Broderick et al. 1985 | Muricide by male rats. Animals were sacrificed 1–2 hrs following the introduction of the mouse into the home cage. 5-HT and its metabolites were assayed in the hypothalamus, thalamus, hippocampus, striatum, cortex and brain stem | Muricidal rats had increased 5-HT (ng/g) in the amygdala and increased 5HIAA in the anterior hippocampus compared to non-muricidal rats. |
Tani et al. 1987 | Muricide by male rats with olfactory bulbectomy, n. raphe or n. accumbens lesioning. Animals were sacrificed immediately after muricide. 5-HT and its metabolites were assayed in the frontal cortex and hypothalamic and amygdaloid nuclei | 5-HT and 5HIAA (ng/mg protein) were not different in muricidal and non-muricidal rats. (5-HT and 5HIAA were decreased in hypothalamic and amygdaloid nuclei of raphe lesioned group. 5HIAA/5-HT was increased in the LH of raphe lesioned, decreased in the central amygdaloid nucleus of n. accumbens group and decreased in LH and mammillary body of OB. |
Nikulina and Popova 1988 | Ranacide in minks. 5-HT and 5HIAA were measured in the amygdala and lateral and medial hypothalami | Continuous access to food was associated with increased 5HIAA in the lateral hypothalamus and amygdala and increased latency for ranacide (15 sec to 1.5 min). Food-deprived minks and those given a single meal did not differ in 5HIAA levels or ranacide latency. |
Peripheral Correlates of Animal Aggression |
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Dominance related Aggression |
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Raleigh et al. 1983 | Group-housed male vervet monkeys | Dominant males have higher concentrations of whole blood 5-HT (ng/ml) and CSF 5HIAA than nondominant males |
Elsworth et al. 1985 | Group-housed male vervet monkeys. Plasma phenylacetic acid was measured in dominant or submissive monkeys | Dominant males had higher concentrations of free and conjugated plasma phenylacetic acid (ng/ml) than lower ranking males. |
CSF correlates of Animal Aggression |
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Dominance-related Aggression |
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Yodyingyuad et al. 1985 | Group-housed malapoin monkeys. CSF 5HIAA and HVA and plasma cortisol were assayed during the formation of a social hierarchy, in established groups and in relation to the daily performance of aggressive behaviors | During the establishment of social hierarchies, males that became lowest in rank had significantly more CSF 5HIAA and HVA (ng/ml) (n=3) than before they were group-housed; 5HIAA levels decreased in certain individuals that became dominant (n=3). In established hierarchies, dominant males and females had less 5HIAA and plasma cortisol than low ranking animals. Daily variations in attacks and threats received did not correlate with CSF 5HIAA in subordinates. Dominant monkeys had higher 5HIAA on days they were overtly aggressive. |
Sahakian et al. 1986 | Pairs of isolated male rats tested in a neutral arena. 5-HT turnover (nmol/ml/h) was estimated with probenecid administration. | CSF tryptophan (nmol/ml) positively correlated with attack bite frequency |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
B. Neuropharmacological Manipulations of 5-HT |
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Animal Studies |
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5-HT synthesis manipulation |
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Isolation-induced Aggression |
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Randt et al. 1975 | Compared two strains of adult male mice that were undernourished in utero. Aggression directed at an olfactory-bulbectomized conspecific. 5-HT turnover estimated with pargyline. | A greater percentage (75%) of previously undernourished DBA but not C57 mice attacked an opponent compared to controls (33%). Although 5-HT turnover was lower in the undernourished group, there was not a systematic difference between aggressive and non-aggressive individuals. |
Rolinski 1975 | Male mice confronting a male conspecific | PCPA (ED50:100 mg/kg i.p.) decreases fighting. |
Eichelman 1981 | Male mice confronting a male conspecific | Mice fed a tryptophan-deficient diet for 4 weeks fought more than controls fed a normal diet or controls fed reduced calories with tryptophan replacement. |
Weinstock and Weiss 1980 | Male mice confronted a group-male intruder in a neutral arena | 5-HTP (10 mg/kg s.c.) elicited aggression in non-aggressive mice and increased attack bite frequency in mice that already were aggressive. |
Lasley and Thurmond 1985 | Male mice confronted a group-housed intruder in a neutral arena |
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| Tryptophan (.50% supplement/10 days) in diet increased aggression without affecting motor activity. |
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Payne et al. 1984 | Male hamsters confronting a group-housed intruder | PCPA (180 mg/kg i.p.) blocked the pro-aggressive effects of prolonged isolation, while 5-HTP (40 mg/kg i.p.) enhanced it |
Drug-induced Aggression |
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Rolinski and Herbut 1979 | Apomorphine-induced aggression in similarly treated pairs of male rats. | Tryptophan (200 mg/kg i.p.) and 5-hydroxytryptophan (100 mg/kg i.p.) decreased fighting frequency. PCPA administered for 3 days (200, 200, 100 mg/kg i.p.) prior to apomorphine also suppressed aggression. |
Carlini and Lindsey 1982 | THC-induced aggression in similarly treated pairs of REM-deprived male rats | Tryptophan (200 mg/kg i.p.) potential aggression. PCPA (300 mg/kg i.p.) pretreatment inhibited aggression. |
Fujiwara and Ueki 1974 | THC-induced muricide in group-housed male rats. | PCPA (300 mg/kg i.p.) pretreatment induced muricide in 70% of non-aggressive, group-housed rats. They also exhibited hyperirritability, hypersexuality and catalepsy. |
Pain-induced Aggression and Defense |
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Rolinski and Herbut 1981 | Electric foot shock-induced fighting in male mice | l-Tryptophan (200–400 mg/kg) did not alter fighting; 5-HTP (100–200 mg/kg) reduced fighting with the lowest dose being the most effective. PCPA (200 mg/kg/day) also reduced fighting. |
Eichelman 1981 | Electric foot shock-induced fighting in male rats | Rats fed a tryptophan deficient diet were more aggressive than controls fed a normal diet or controls fed a low-calorie diet with tryptophan supplements. Pain sensitivity and whole brain levels of 5-HT were also reduced. |
Ellison and Bresler 1974 Conner et al. 1973 | Electric foot shock-induced fighting in male rats | PCPA (100 mg/kg s.c./2 days for 11 days) increased fighting and decreased locomotion, rearing and grooming. Higher doses (320–920 mg/kg s.c./6 days) had no effect on fighting behavior. |
Brain lesion-induced aggression |
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Dominguez and Longo 1969, 1970 | Septal lesion-induced aggression in male rats | PCPA (300 mg/kg) tamed hyperirritability in septal lesioned rats; When administered before septal lesions, PCPA (300–600 mg/kg) and AMPT (25–200 mg/kg) did not prevent hyperirritability, and higher doses of AMPT produced sedation. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Defensive Aggression induced by brain stimulation |
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MacDonnell et al. 1971; Dubinsky et al. 1973; Katz and Thomas 1976 | ''Sham rage" following electrical hypothalamic stimulation in male and female cats | PCPA (150 mg/kg i.p. daily for 3 days) or 5-HTP (5 mg/kg i.p.) had no effect on aggression. Higher doses of PCPA (250–300 mg/kg i.p. daily for 2–3 days) potentiated growling and biting inanimate objects or experimenter. |
Aggression by Resident toward Intruder |
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Thurmond et al. 1979, 1980 | Male group-housed mice isolated over night confronted a naive intruder. Diets were supplemented with amino acid precursors. | l-Tryptophan (0.25, 0.5% for 2 weeks) supplements increased aggression. Longer administration (2–5 weeks) of l-tryptophan (4%) decreased aggression. Whole brain levels of 5-HT and 5HIAA were increased at all concentrations of l-tryptophan, while NE and DA were decreased. |
Female Aggression |
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Svare and Mann 1983 | Lactating mice confronting a conspecific | DL PCPA (400 mg/kg/day for 6 days; route of administration not stated) decreased the proportion of mice attacking an intruder. |
Ieni and Thurmond 1985 | Maternal aggression in mice confronting a male opponent | PCPA (200–400 mg/kg, i.p.) and 5-HTP (100 mg/kg, i.p.) increased the latency to attack and reduced the number of attacks. |
Dominance-related Aggression |
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Sheard 1970a | Male rats placed into a chamber with a male and female rat and a mouse. | PCPA (320 mg/kg i.p.) increased sexual and aggressive behavior, while decreasing whole brain 5-HT and 5HIAA. Chronic lithium pretreatment (5 meq/kg for 5 days) blocked PCPA effects on behavior without blocking serotonergic depletion. |
Rolinski 1975 | Male and female rats confronting a conspecific in a neutral environment | PCPA (400 mg/kg i.p.) increased aggressive behavior in both males and females. |
Raleigh et al. 1980 | Group-housed monkeys | PCPA (80 mg/kg/day) administered for 14 days increased aggression in vervet monkeys; concurrent administration of 5-HTP (40 mg/kg/day) further increased aggression while tryptophan (20 mg/kg/day) had no effect. Daily PCPA administration (no dose specified) did not affect social behavior in macaques. |
Chamberlain et al. 1987 | Group-housed male and female vervet monkeys. Aggression occurring spontaneously and during food competition was assessed. | Males fed a tryptophan-free diet were more spontaneously aggressive than controls. During food competition, males fed a tryptophan-free diet were more aggressive, while males and females fed a diet with excess tryptophan were less aggressive than controls. |
Killing |
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McCarty et al. 1976 | Cricket-killing in male and female grasshopper mice | PCPA (50 mg/kg/day for 5 days i.p.) decreased duration of predatory attack and increased attack latency |
DiChiara et al. 1971; Eichelman and Thoa 1973; Conner et al. 1973 Miczek et al. 1975 Rolinski 1975; Gibbons et al. 1978; Berzsenyi et al. 1983; Pucilowski and Valzelli 1986; Isel and Mandel 1989; Molina et al. 1987 | Muricide in male and female rats | PCPA decreased attack latency and increased the percentage of male and female rats that killed mice; whole brain 5-HT and 5HIAA were concomitantly decreased. |
Kulkarni 1970; DiChiara et al. 1971; Bocknik and Kulkarni 1974; Gibbons et al. 1978 | Isolated male rats selected for muricidal behavior | 5-HTP (30, 100, 200 mg/kg i.p.) decreased the percentage of animals that killed mice. High doses (150, 200 mg/kg i.p.) of the decarboxylase inhibitor, Ro4-4602, blocked 5-HTP-induced inhibition whereas low doses (5, 10 mg/kg i.p.) enhanced it. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Gibbons et al. 1979 | Muricide in isolated male rats. | A tryptophan-free diet (4–6 days) induced muricide in 60% of non-muricidal rats and facilitated killing in muricidal rats. Whole brain 5-HT and 5HIAA were concomitantly decreased. |
Gibbons et al. 1981 Broderick and Lynch 1982 | Muricide in isolated male rats. 5-HT turnover was assessed with tranylcypromine. | Acute (100–800 mg/kg i.p.) and long-term l-tryptophan (100 mg/kg i.p. for 7 days) decreased muricide without affecting food intake or motor function. Forebrain and hindbrain 5-HT turnover was concomitantly increased. |
Copenhaver et al. 1989 | Filicide in nulliparous female Sprague-Dawley rats | PCPA (400 mg/kg s.c.0 induced filicide. |
Nikulina and Popova 1988 | Predatory aggression in the mink | 5-HTP (50, 100 mg/kg i.p.) increased levels of 5-HT in the hypothalamus and midbrain and suppressed predatory aggression; 100 mg/kg also suppressed locomotor activity. |
5-HT releasers |
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Experimenter-provoked Aggression |
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Raleigh et al. 1986 | Individually-housed male vervet monkeys. Aggression was elicited by an experimenter staring at the subject. | Chronic fenfluramine (1–4 mg i.m. daily for 10 weeks) decreased plasma 5-HT and CSF 5HIAA and increased aggressive threats. |
Pain-induced Aggression and Defense |
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Rolinski and Herbut 1981 | Electric foot shock-induced fighting in male mice | Fenfluramine (5–10 mg/kg) dose dependently reduced aggressive behavior |
Sheard 1976 | Electric foot shock in rats (sex unspecified) | Acutely, paracloramphetamine (PCA) (2.5–10 mg/kg) suppresses fighting while over time fighting frequency and intensity are increased. Neurochemically, acute PCA releases 5-HT while over time it inhibits TH and is neurotoxic. |
Dominance-related Aggression |
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Raleigh et al. 1986 | Individually-housed male vervet monkeys. Aggression directed toward an inaccessible conspecific was measured. | Chronic fenfluramine (1–4 mg i.m. daily for 10 weeks) decreased plasma 5-HT and CSF 5HIAA and increased aggressive threats |
5-HT receptor agonists |
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Experimenter-elicited Aggression |
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Maler and Ellis 1987 | High frequency electric organ discharges in South American electric fish elicited by simulated electric signals. | 5-HT (.1 µg i.c.v.) decreased aggressive signalling |
Isolation-induced Aggression |
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Lindgren and Kantak 1987; Olivier et al. 1989 | Male mice confronting a group-housed intruder | 5-HT1A agonists, 8-OH-DPAT (0.05–6.25, s.c.), 5-Me-ODMT (0.3–10 mg/kg, i.p.), ipsapirone (0.3–10 mg/kg i.p.), buspirone (0.3–10 mg/kg) and 5-methoxytryptamine (2.5–20 mg/kg, i.p.) reduced a composite measure of aggression; at higher doses, 8-OH-DPAT and 5-Me-ODMT enhanced avoidance-defensive behaviors. |
Pain-induced Aggression and Defense |
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Rolinski and Herbut 1981 | Electric foot shock-induced fighting in made mice | 5-methoxytryptamine (2 mg/kg i.p.) increased the ferocity and number of attacks and decreased spontaneous motor activity; quipazine (10 mg/kg i.p.) did not alter aggression. |
Rodgers 1977; Ray et al. 1983 | Electric foot shock in male rats | Intraventricular 5-HT (25 µg/µl) increased fighting without affecting pain sensitivity. 5-HT (10 µg/µl) bilaterally infused into the corticomedial but not basolateral amygdala decreased attack frequency by 40%; sensitivity to footshock was concomitantly decreased. |
Drug-Induced Aggression |
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Golebiewski and Romaniuk 1985 | Intrahypothalamic carbachol-induced "sham rage" in male and female cats | 5-HT (5 µg) bilaterally infused into the anterior hypothalamus decreased the frequency and duration of carbachol-induced growling. |
Hahn et al. 1982 | Apomorphine-induced aggression in male rats chronically treated with clonidine (5 mg/ml in drinking water, 7 days). | 5-HT1B agonist mCPP (0.3–10 mg/kg, i.p.) dose dependently reduced aggression induced by apomorphine and clonidine at doses that did not alter behavior in control rats. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Aggression by Resident Toward Intruder |
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Olivier et al., 1984 | Male rats | Fluprazine (5–20 mg/kg) dose dependently reduced aggressive threats and attacks. |
Lindgren and Kantak, 1987 | Male mice confronting a group-housed intruder. | 5-HT3 agonist, quipazine (5–25 mg/kg, i.p.), reduced aggressive threats and attacks. |
Haug et al., 1990 | Group-housed female mice confronting a lactating female resident | 8-OH-DPAT (200, 250 mg i.p.) decreased attack frequency and increased attack latency without affecting locomotor activity. |
Dominance-related Aggression |
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Kennett et al., 1989 | Social interaction test in pairs of similarly treated rats | 5-HT1B agonist, mCPP (0.5–1 mg/kg, i.p.) reduced boxing, biting as well as non-aggressive social behaviors whereas TFMPP (0.2–1.0 mg/kg, i.p.) did not; the antagonist cyanopindolol (6 mg/kg, s.c.) did not reverse the effects of mCPP. |
Killing |
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Rolinski 1975; Applegate 1980; Berzsenyi et al. 1983; Pucilowski et al. 1985; Molina et al. 1986; Pucilowski and Valzelli 1986; Strickland and DaVanzo 1986 | Muricide in rats induced by isolation or olfactory bulbectomy | 5-HT (10 µg i.c.v) increased the latency to kill mice. 5-HT agonists, 8-OH-DPAT and 5-Me-ODM reduced the percentage of muricidal animals. Bilateral microinjection of 5-HT3 agonist, quipazine (20 µg/µl) into the corticomedial amygdala reduced the latency to kill. |
Applegate 1980 | Muricide in rats induced by intraventricular 5,7-DHT | 5-HT (.5, 10 µg i.c.v.) increased the latency to kill mice. |
5-HT Antagonists |
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Isolation-induced Aggression |
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Malick and Barnett 1976 | Isolated male mice confronted another isolate within the home cage | Methiothepin (0.04 mg/kg, ED50), mianserin (0.5 mg/kg, ED50), methysergide (1.0 mg/kg, ED50), cyproheptadine (1.1 mg/kg, ED50), pizotyline (1.5 mg/kg, ED50), xylamidine (2.5 mg/kg, ED50), and cinanserine (7.3 mg/kg, ED50) prevented fighting without altering motor activity or performance in the inlined screen test. |
Weinstock and Weiss 1980 | Male mice confronted a group-housed intruder within a neutral arena | Methysergide (ED50=4.1 mg/kg s.c.) decreased aggression without decreasing locomotor activity. |
Pain-induced Aggression and Defense |
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Rodgers 1977 | Electric foot shock-induced aggression in rats (sex unspecified) | Methysergide (5 µg/µl) bilaterally infused into the corticomedial but not basolateral amygdala increased attack frequency by 46%. Sensitivity to footshock was concomitantly increased. |
Drug-Induced Aggression |
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Rolinski and Herbut 1979 | Apomorphine-induced aggression in similarly treated pairs of male rats. | Cyproheptadine (1, 5 mg/kg i.p.) potentiated aggression. Rats receiving subthreshold doses of apomorphine became aggressive following either cyproheptadine or metergoline (1.5 mg/kg i.p.). |
Hahn et al. 1982 | Apomorphine-induced aggression in male rats chronically treated with clonidine (5 mg/ml in drinking water x 7 days) | 5-HT1 antagonist, metergoline (3 mg/kg, i.p.) enhanced aggression induced by apomorphine and clonidine at doses that did not alter behavior in control rats |
Golebiewski and Romaniuk 1985 | Intrahypothalamic carbachol-induced "sham rage" in male and female cats | Methysergide (10 µg) bilaterally infused into the anterior hypothalamus increased carbachol-induced growling. |
Aggression by Resident toward Intruder |
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Winslow and Miczek 1983; Lindgren and Kantak 1987; Haney and Miczek 1989 | Male mice confronting group-housed intruder | Methysergide (3.0, 10.0 mg/kg i.p.), a non-specific 5-HT antagonist, decreased attacks, aggressive threats and locomotion. The 5-HT1 antagonist mianserin (0.5–5 mg/kg, i.p.) and the 5-HT2 antagonist ketansarin (1–10 mg/kg, i.p.) decreased aggression at doses which did not decrease locomotion. |
Female Aggression |
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Ieni and Thurmond 1985 | Maternal aggression in mice | 5-HT1 antagonists, mianserin (2–4 mg/kg, i.p.), methysergide (4 mg/kg, i.p.) and methiopin (0.25–0.5 mg/kg) decreased attack behavior compared to controls. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Dominance-related Aggression |
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Kennett et al,. 1989; File and Johnston 1989 | Social interaction test in pairs of similarly treated rats under low light and familiar conditions | 5-HT1 antagonists, mianserin (2 mg/kg, s.c.), cyproheptadine (2 mg/kg, s.c.), and metergoline (2.5 mg/kg, s.c.) prevented reduction in interaction time elicited by 5-HT1B agonists, mCPP and TFMPP (0.1–1 mg/kg, i.p.). 5-HT3 antagonists, ICS 205 930 (0.05–1 mg/kg, s.c.), GR 38032F (0.1–1 mg/kg, p.o. and zacopride (0.01–1 mg/kg, i.p.) did not alter social interactions nor did they prevent the reduction in interaction time elicited by 5-HT1B agonists, mCPP and TFMPP (0.1–1 mg/kg, i.p.). |
Kennett et al,. 1989 | Social interaction test in pairs of similarly treated rats | 5-HT1 antagonists, ritanserin (0.6 mg/kg, s.c.) and cyanopindolol (6 mg/kg, s.c.), and 5-HT2 antagonist, ketanserin, (0.2 mg/kg, s.c.) did not alter social interactions nor did they prevent the reduction in interaction time elicited by 5-HT1B agonists, mCPP and TFMPP (0.1–1 mg/kg, i.p.). |
Killing |
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Pucilowski et al. 1985; Strickland and Da Vanzo 1986 | Isolation-induced muricide in male rats selected for their aggressivity | 5-HT1 antagonist, mianserin (ED50=10.47) decreased muricide. |
5-HT lesioning |
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Isolation-induced Aggression |
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Poschlová et al. 1975; Poschlová et al. 1977; Matte 1982 | Male mice confronting a non-aggressive opponent | Administration of 5,6-DHT (25 µg i.c.v) increased alert postures and reduced social behaviors, including aggressive threats and attacks. |
Pain-induced Aggression and Defense |
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Pucilowski and Valzelli 1986 | Electric foot shock in male rats | Electrolytic lesions of the dorsal but not medial raphe nucleus increased the number of fighting bouts. 5,7-DHT infused into the n. accumbens did not affect aggressive behavior. |
Drug-induced Aggression |
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Palermo Neto et al. 1975 | Chronic THC-induced aggression in pair-housed, ovariectomized female rats receiving hormonal replacement. Aggression toward untreated cagemate assessed. 5-HT turnover measured with pargyline. | Chronic cannabis increased aggression while decreasing whole brain levels of 5-HT. Not clear if decreased 5-HT preceded fighting, or was a consequence of fighting. |
Romaniuk et al. 1987 | Carbachol-induced growling in male and female cats | Raphe lesioning increased growling, while decreasing concentrations of NE, 5-HT and 5HIAA and increasing DA. |
Aggression by Resident toward Intruder |
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Winslow and Miczek 1983 | Male, pair-housed mice encountering a male conspecific | 24 post-administration, PCA (50 mg/kg i.p.) enhanced attack, aggressive threat and locomotion. |
Dominance-related Aggression |
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Ellison 1976 | Male rats living in colonies with established dominance hierarchies | Individual animals receiving 5,6-DHT (10 µg/day i.c.v. for 3 days) showed increased motor, sexual and aggressive behavior and increased in dominance status over a 25 day period |
Killing |
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Banerjee 1974; Breese and Cooper 1975; Vergnes et al. 1973, 1988; Applegate 1980; Marks et al. 1977; Pucilowski and Valzelli 1986; Isel and Mandel 1989; Yamamoto et al. 1988 | Muricide in male rats | Intraventricular 5,7-DHT or specific lesioning of the raphe nucleus or the intrahypothalamic ascending 5-HT pathways increased the percentage of rats that killed mice, especially when NE depletion was blocked by the concurrent administration of MAO-inhibitors. The combined administration of a 5-HT antagonist and an NE precursor inhibited muricide. Muricide was not induced when 5,7-DHT was limited to the n. accumbens or if rats were handled prior to the administration of 5,7-DHT. |
Liou et al. 1985 | Olfactory bulbectomy-induced muricide in male rats | The suppressive effects of ECS on muricide were not altered with raphe nucleus lesions |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Human Studies |
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Criminal Violence |
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Bioulac et al. 1980 | XYY patients arrested for crimes ranging from vagrancy to assault (n=6) were administered L-5-hydroxytryptophan (1.5–1.85 g/day) for 5 months. | Tryptophan administration increased CSF 5HIAA and resulted in a clinically observed reduction in aggression in 4 of 6 patients. No statistics were reported. |
Inpatient Studies |
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Coccaro et al. 1989 | Fenfluramine (60 mg p.o.) was administered to "normal" controls and to patients with either a personality or a major affective disorder. Plasma PRL following fenfluramine administration was used as an index of central 5-HT activity. | PRL response was significantly reduced in both sets of patients in comparison to controls. Scores on aggression scales negatively correlated with plasma PRL levels in patients with personality disorder but not major affective disorder. Past history of suicide attempts correlated with reduced PRL response in both groups of patients. |
Volavka et al. 1990 | Tryptophan (up to 6 g/day p.o. for 25–35 days) or placebo treatment in violent male and female psychiatric patients. Antipsychotics or sedatives were concurrently administered to control violent behavior | Tryptophan had no effect on the number of violent incidents (agitation, verbal assault, assault on others or self, and property assault) compared to the placebo group. However the tryptophan group apparently required fewer drug treatments to control violence than the placebo group. |
Outpatient Studies |
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Fishbein et al. 1989 | Fenfluramine (60 mg p.o.) was administered to male polydrug users seeking treatment for addiction. Subjects were assigned to a high and low aggressive group, based on psychometric testing. Plasma PRL and cortisol following fenfluramine administration used as an indice of central 5-HT activity. | When adjusted for differences in baseline, PRL and cortisol in the plasma were elevated in subjects scoring high on tests of aggression and impulsivity. The neuroendocrine response to fenfluramine was better correlated with impulsivity than aggression. |
C. 5-HT Correlates of Human Aggression and Violence |
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Peripheral correlates of aggression in humans |
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Inpatient studies |
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Subrahmanyam 1975 | Schizophrenic, manic-depressive psychotics and healthy controls were compared: 6 out of 60 schizophrenics were in an "acute aggressive state". Urinary 5HIAA was measured. | Urinary 5HIAA appeared elevated in aggressive schizophrenics in comparison to both controls and non-aggressive schizophrenics. No statistics reported. |
Greenberg and Coleman 1976 | Plasma 5-hydroxyindole (5HI) was measured in 24 hyperactive, institutionalized mentally retarded men and women before and after drug treatment. Individual patients were compared to age- and sex-matched controls. Clinical and staff reports were used as dependent variables. | Baseline 5HI levels were depressed in 83% of patients compared to controls. In 63% of these patients, decreases in hyperactivity and aggression correlated with increases in 5HI. |
Outpatient Studies |
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Kent et al. 1988; Brown et al. 1989 | 5-HT uptake in blood platelets was measured in male outpatients seeking treatment for frequent bouts of verbal and physical aggression and age-and sex-matched healthy controls (n=15) | In 11/15 cases, platelet 5-HT uptake (pmol/2 x 107 platelets) was slightly lower in aggressive patients compared to controls. 5-HT uptake negatively correlated with scores on impulsivity but not anger scales. |
Leckman et al. 1990 | CSF 5HIAA was measured in an adult male and female obsessively preoccupied with violent thoughts. Imagery but not behavior was overtly aggressive. | CSF 5HIAA was significantly reduced in patients with violent thoughts compared to normal and psychiatrically disturbed populations. |
Criminal Violence |
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Raisanen et al. 1984 | Urinary bufotenine (5-HT metabolite) was measured in male offenders arrested for murder or attempted murder (n=48) and healthy controls. | Urinary bufotenine (nmol/g creatinine) was higher in violent patients compared to controls. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Virkkunen and Narvanen 1987 | Plasma 5-HT and tryptophan were measured before and after a glucose tolerance test in healthy controls and violent incarcerated male offenders, diagnosed with either intermittent explosive disorder (n=6) or antisocial personality. | Convicts with intermittent explosive disorder had higher plasma tryptophan levels (mmol/l) than the other groups. Following glucose administration, convicts with intermittent explosive disorder had higher tryptophan and insulin (30 min post injection) than normals. 5-HT levels did not differ between groups. |
CSF correlates of aggression in humans |
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Inpatient studies |
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Subrahmanyam 1975 | Schizophrenic, manic-depressive psychotics and healthy controls were compared: 6 out of 60 schizophrenics were in an ''acute aggressive state". CSF 5HIAA was measured. | CSF 5HIAA (ng/ml) in acute, aggressive schizophrenics was comparable to controls but higher than non-aggressive acute schizophrenics. No statistics reported. |
Brown et al. 1979 | CSF 5-HT and 5HIAA were measured in military men diagnosed with borderline personality disorder without affective illness (n=26). | CSF 5HIAA (ng/ml) did not differ in patients with borderline personality disorder and normal controls. If just the patients are analyzed, there is a negative correlation between scores based on the life history of aggression and CSF 5HIAA. |
Brown et al. 1982 | CSF 5-HT and 5HIAA were measured in military men diagnosed with borderline personality disorder without affective illness (n=12). | CSF 5HIAA (ng/ml) negatively correlated with psychopathic deviate scores on the MMPI (-.77) and with scores of aggression based on life history (-.53); CSF 5HIAA did not covary with the Buss-Durkee Inventory for aggression. |
Criminal Violence |
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Bioulac et al. 1980 | CSF 5-HT was measured in healthy controls (n=5) and XYY patients arrested for crimes ranging from vagrancy to assault (n=6). Probenicid was used to estimate turnover. | Following probenicid administration, XYY patients had less 5HIAA (ng/ml) than controls; baseline 5HIAA and HVA levels did not appear to differ between groups. |
Linnoila et al. 1983 | CSF 5HIAA was assayed in men convicted of violent crime. Subjects were subdivided into categories specifying the pre-meditated or impulsive nature of the criminal act. | Impulsive violent offenders had lower CSF 5HIAA (pmol/ml) than those in the premeditated group. When subjects were re-categorized based on the number of crimes committed, CSF 5HIAA was lower in the group that committed more than 1 violent act. |
Lidberg et al. 1985 | CSF 5HIAA, HVA and MHPG were assayed in homicidal convicts, suicidal patients and healthy controls. | Suicidal patients had lower concentrations of 5HIAA (nmol/l) than controls. Overall, metabolite concentrations in homicidal convicts did not differ from controls. Post-hoc categorization of convicts indicate men who killed a sexual partner had lower levels of 5HIAA than controls. |
Linnoila et al. 1989; Virkkunen et al. 1989a,b | Measured CSF 5HIAA, HVA and MHPG in male alcohol abusers, imprisoned for manslaughter or arson | CSF 5HIAA (nmol/l) was lower in imprisoned males compared to healthy controls. Prisoners having a family history of alcoholism had lower CSF 5HIAA than those that did not. Subjects with a history of suicidal attempts had lower CSF 5HIAA and MHPG than those that did not. |
Behavioral Disorders in Juveniles |
|
|
Kruesi et al. 1990 | Measured CSF 5HIAA, HVA and MHPG in children and adolescents diagnosed with either disruptive behavioral disorder or obsessive compulsive disorder | Patients with disruptive behavior disorders had lower CSF 5HIAA (pmol/ml) and higher aggression than age-, sex-, and race-matched patients with obsessive-compulsive disorder. CSF 5HIAA negatively correlated with scores on 2/9 measures of aggression in subjects with disruptive behavior disorders. |
TABLE 4: GABA
References | Methods and Procedures | Results and Conclusions |
A. GABA Correlates of Animal Aggression |
| |
Whole Brain Measurements |
|
|
Aggression by Resident toward Intruder |
|
|
Earley and Leonard 1977 | Testosterone-treated (1 mg/kg) or cyproterone acetate-treated (1 mg/kg) group housed and untreated isolated male mice | Housing conditions alter brain concentrations of GABA as well as aggression. Aggressive response was inversely related to GABA content in olfactory bulb and striatum. Testosterone administration increased GABA concentrations in group-housed mice and reduced aggressive attacks received by untreated isolates |
Female Aggression |
|
|
Haug et al. 1987 | Confrontations between female C57, C3H, B6HEF1 and HEB6F1 strain resident mice vs lactating intruders | No relationship was found between aggressiveness and brain GABA concentration |
Killing |
|
|
Mack et al. 1975 | Predatory aggression in male rats | Brain GABA levels were reduced in the olfactory bulbs of mouse killing rats compared to non-killing rats |
Regional brain measurements |
|
|
Isolation-induced aggression |
|
|
Simler et al. 1982 | Aggression in pairs of DBA/2 and C57 strain male mice either group housed or single housed for 8 weeks | Non-aggressive C57 mice and aggressive DBA/2 mice showed decreases in GABA concentrations in septum, striatum, olfactory bulb and posterior colliculus following isolation. Compared to C57 mice, DBA/2 mice showed high levels of aggression, an increase in GABA concentrations in the anygdala, and reduced GABA concentrations in olfactory bulb and striatum |
Female Aggression |
|
|
Potegal et al. 1982 | Confrontations between aggressive and non-aggressive ovariectomized female resident hamsters vs methotrimeprazine-treated intruder hamsters | Aggressive females had 15–25% higher GABA concentrations in midregions of brain (limbic, striatal, and diencephalic structures) than non-aggressive females |
Aggression by Resident toward Intruder |
|
|
Haug et al. 1984 | Confrontations between three resident castrated or sham-operated males vs. lactating female intruders in three strains of mice | Brain GABA levels were increased in the hypothalamus, olfactory bulbs, and amygdala in castrates of the most aggressive strain (C57); C57 and C3H castrates displayed shorter attack latencies and increased attacks than sham-operated animals |
Muñoz-Blanco et al. 1986 | Comparison between aggressive and non-aggressive strains of female bulls. Synaptosomes from 7 brain regions were measured for amino acid content | Compared to the non-aggressive strain, Spanish fighting-bulls had higher GABA concentrations (120%) in the thalamus and slightly lower concentrations in the hypothalamus (69%), caudate nucleus (66%) and corpus striatum (82%). A higher ratio of excitatory (glutamate, aspartate) to inhibitory (GABA, glycine) neurotransmitter amino acids was found in the aggressive strain. |
Killing |
|
|
DaVanzo et al. 1986 | Predatory aggression in isolated and group housed male rats. | Mouse-killing rats showed slight increases (32–34%) in muscimol binding in the amygdala compared to non-killing rats regardless of housing condition. |
B. Neuropharmacological manipulations of GABA |
| |
GABA Synthesis Manipulations |
|
|
Isolation-induced Aggression |
|
|
Puglisi-Allegra and Mandel 1980 | Isolation-induced aggression in DBA/2 strain male mice; aggression measured with automated bite detector. | Low doses of a GABA-T inhibitor, valproate (200 mg/kg) or GABA reuptake blocker, nipecotic acid (125 mg/kg), did not alter aggression on initial administration, but inhibited aggression on the second day. Higher doses (300 mg/kg valproate) reduced aggression all 3 days. |
References | Methods and Procedures | Results and Conclusions |
Poshivalov 1981 | Isolation-induced aggression in male mice; aggression measured with automated bite detector | GABA synthesis inhibitor, thiosemicarbazide (1 mg/kg) increased probability of attacks; GABA-T inhibitor, gamma-acetylenic GABA (75–100 mg/kg) reduced attack, threat and ambivalent behaviors (e.g., tail rattle) |
Simler et al. 1983 | Isolation-induced aggression in DBA/2 and C57 strain male mice | A GABA-T inhibitor, valproate (300 mg/kg) blocked aggression in DBA/2 mice in a time-dependent manner peaking at 75 min. post injection; decreases in aggression paralleled increased concentrations of GABA in olfactory bulb, striatum, posterior colliculus and septum |
Sulcova and Kršiak 1981 | Isolation-induced aggression or timidity in male mice | GABA-T inhibitors, valproate (25–200 mg/kg) and aminooxyacetic acid (1–9 mg/kg) dose dependently reduced aggressive threats, attacks and tail-rattle in aggressive mice, and defensive escape behaviors in timid mice |
DaVanzo and Sydow 1979 | Isolation-induced aggression in male mice | GABA-T inhibitors aminooxyacetic acid (20–40 mg/kg) and gamma-acetylenic GABA (100–150 mg/kg) dose-dependently prolonged latency to attack and increased whole brain GABA concentration. |
Oehler et al. 1985 | Isolation-induced aggression in male mice | Initial administration of a GABA-T inhibitor, valproate (200 mg/kg/day in drinking water) reduced viewer rated aggression, but was inactive after chronic administration (4 weeks). |
Pain-induced Aggression |
|
|
Rodgers and Depaulis 1982 | Electrical foot shock-induced aggression in pairs of male rats | Valproate (100–200 mg/kg), a reversible GABA-T inhibitor, did not alter shock-induced fighting behavior; g-vinyl GABA (100–200 mg/kg), an irreversible GABA-T inhibitor dose dependently reduced fighting. |
Puglisi-Allegra et al. 1981 | Electrical tail shock-induced aggression in C57 and DBA/2 male mice | GABA-T inhibitor, valproate (200–250 mg/kg) inhibited shock-induced biting whereas GAD (glutamic acid decarboxylase) inhibitor, DL-allylglycine (15–25 mg/kg) elicited shock-induced biting in 20–21 week old, highly aggressive C57 mice. Biting in non-aggressive DBA/2 mice was unchanged. |
Drug-induced Aggression |
|
|
Arnt and Scheel-Krüger 1980 | GABA receptor antagonist-induced self directed aggression in male rats | Systemic g-acetylenic GABA (GABA-T inhibitor) blocked bicuculline-induced (30–60 ng/ml/rat) and picrotoxin-induced (50–100 ng/ml/rat) self-biting |
Aggression by Resident toward intruder |
|
|
Haug et al. 1980 | Confrontations between three intact or gonadectomized male and female mice vs. lactating female intruders | GABA-T inhibitor, valproate (200–300 mg/kg) prevented attacks by intact resident males or females towards lactating intruders, and reduced aggression in castrated males; Valproate increased GABA concentrations in the hypothalamus (40–50%) in intact and gonadectomized male and female mice, and in olfactory bulbs (50%), and amygdala (70%) in intact males. Female and male gonadectomized mice showed increased (85 and 70% respectively) GABA content in posterior colliculus |
Killing |
|
|
Mack et al. 1975 | Predatory aggression in male rats | Valproate (200 mg/kg) abolished mouse killing behavior in 90% of killer rats, but was ineffective in olfactory bulbectomized killer rats. Intraolfactory bulb microinjection of valproate (25 mg) blocked mouse killing behavior 30 minutes to 3 hours post injection. GABA (200 mg/kg) immediately abolished mouse killing behavior, but effects lasted less than 1 hour. Simultaneous injection of valproate with GABA blocked mouse killing immediately and persisted for 4 hours post injection. |
References | Methods and Procedures | Results and Conclusions |
Potegal et al. 1983 | Predatory aggression and viewer-rated aggression directed at experimenter in isolated male rats | Microinjections (0.005–0.5 mg) of GABA synthesis inhibitor, thiosemicarbazide, into the septum dose-dependently decreased latency to kill mice, and increased irritability (escape, biting and vocalizations). |
Depaulis and Vergnes 1984 | Predatory aggression in male rats | g-Vinyl GABA (200–400 mg/kg) (irreversible inhibitor of GABA-T) and nipecotic acid (GABA reuptake blocker) reduced mouse-killing in experienced rats, but increased incidence of mouse killing in naive, food-deprived rats; reductions in mouse-killing were concurrent with sedation as measured in open field tests and with photobeam interruptions. Dipropylacetate (reversible inhibitor of GABA-T and succinic semialdehyde) was inactive |
Molina et al. 1986 | Predatory aggression in isolated male rats | Intraolfactory administration (0.15 mmol/rat) of GABA-T inhibitors: DPA and g-vinyl GABA reduced mouse killing animals to 5–30% of previous levels 30 minutes to 3 1/2 hours after administration. GABA reuptake blockers were less effective at reducing animals displaying mouse killing; nipecotic acid amide (1–2 hrs post administration) and guvacine (1–4 hours post administration) reduced mouse killing to 40–60% of previous levels. |
GABA Agonists |
|
|
Isolation-induced Aggression |
|
|
Puglisi-Allegra and Mandel 1980; Sulcova and Kršiak 1980; Poshivalov 1981 | Aggression in male mice; measured with an automated bite detector or by direct observation | Muscimol (0.2–1.5 mg/kg), a GABA receptor agonist, piracetam (300–1500 mg/kg), a cyclized derivative of GABA, and phenibut (50–100 mg/kg) and phenylpyrrolidon (50 mg/kg), GABA analogues, reduced attack, threat and ambivalent behaviors (e.g., tail rattle) and reduced defensive and alert postures. In timid mice, a low dose of piracetam (300 mg/kg) was ineffective, whereas the high dose (1500 mg/kg) reduced defensive postures and escapes. In another study, piracetam, increased aggression (200 mg/kg/day in drinking water), but also increased locomotor activity |
Pain-induced Aggression |
|
|
Puglisi-Allegra et al. 1981 | Electric tail shock-induced aggression in C57 and DBA/2 strain male mice | GABA agonist, muscimol (0.5–1 mg/kg), inhibited shock-induced biting in aggressive C57 mice, and did not alter biting in non-aggressive DBA/2 mice |
Brain-lesion induced Aggression |
|
|
Breese et al. 1987 | 6-OHDA lesion-induced self directed aggression in rats | Bilateral microinjections of GABA receptor agonist, muscimol (30 ng/rat), into substantia nigra produced self biting and lacerations in 2 of 11 controls and in all neonatally 6-OHDA-lesioned rats; this behavior did not occur in adult lesioned rats |
Aggression by Resident toward Intruder |
|
|
Depaulis and Vergnes 1985 | Resident-intruder confrontations in male rats | GABA agonist, THIP (1.25–2.5 mg i.c.v.) induced attack and threat behaviors compared to non-aggressive control |
References | Methods and Procedures | Results and Conclusions |
Killing |
|
|
Depaulis and Vergnes 1983, 1984; Molina et al. 1986 | Predatory aggression in male rats | GABAA agonist, THIP (2.5–5 mg/5ml i.c.v.) reduced latencies to attack and kill mice and induced mouse killing behavior in 60% of non-muricidal rats. THIP did not alter mouse-killing in experienced rats, but increased incidence of mouse killing in naive, food-deprived rats. Intraolfactory administration (0.15 mmol/rat) of muscimol, THIP, and isoguvacine also reduced the percentage of animals showing mouse killing to 25–50%. |
Delini-Stula and Vassout 1978 | Olfactory bulb ablation-induced predatory behavior in male rats | GABA agonists; baclofen (3–10 mg/kg) reduced mouse killing in normal and lesioned rats, whereas muscimol (0.75–1.5 mg/kg) and GABA-acetylester (10–50 mg/kg) reduced mouse killing only in normal rats |
Arnt and Scheel-Krüger 1980 | GABA receptor antagonist-induced self directed aggression in male rats | Concurrent microinjections of GABA agonists muscimol and THIP into the substantia nigra blocked bicuculline-induced (30–60 ng/ml/rat) and picrotoxin-induced (50–100 ng/ml/rat) self-biting. |
GABA Antagonists |
|
|
Isolation-induced Aggression |
|
|
Poshivalov 1981 | Male mice; aggression measured with a bite detector | GABA receptor antagonist picrotoxin (1 mg/kg) increased probability of attacks and bicuculline increased number of attacks at a low dose (0.5 mg/kg) and reduced threats and attacks at higher doses (1–1.5 mg/kg) |
Pain-induced Aggression |
|
|
Puglisi-Allegra et al. 1981 | Electric tail shock-induced aggression in C57 and DBA/2 strain male mice | GABA antagonist, picrotoxin (0.25 mg/kg) elicited shock-induced biting in non-aggressive, 10 week old, C57 and 20 week old DBA/2 mice. |
Rodgers and Depaulis 1982 | Electric foot shock-induced aggression in male rats | Bicuculline (0.25–4 mg/kg), a competitive GABA receptor antagonist, reduced aggression, but effects were variable. Picrotoxin (0.125–2 mg/kg), a noncompetitive GABA receptor antagonist, had a biphasic effect on aggression, where the low dose (0.125 mg/kg) enhanced fighting and higher doses reduced it dose dependently. |
Drug-induced Aggression |
|
|
Arnt and Scheel-Krüger 1980 | GABA receptor antagonist-induced self directed aggression in male rats | Bilateral microinjection of bicuculline (30–60 ng/ml/rat) and picrotoxin (50–100 ng/ml/rat) into the substantia nigra produced self-biting. |
Aggression by Resident toward Intruder |
|
|
Depaulis and Vergnes 1985, 1986 | Male rats confronting a male conspecific | GABA antagonist, bicuculline (62.5–125 ng i.c.v.) reduced aggressive threats and attacks, and increased defensive postures compared to non-aggressive controls. Microinjection of GABA antagonist, picrotoxin (25–50 ng/0.25 ml/rat) into PAG produced a shift from offensive to defensive behaviors when intruder was located contralaterally from injection site. |
Female Aggression |
|
|
Hansen and Ferreira 1986 | Maternal aggression in female rats | Bilateral microinjections of GABA receptor antagonist, bicuculline (60 ng/ml), into the VMH or amygdala reduced aggressive threats, attacks and bites directed at intruder male; defensive freezing behavior was not altered. |
Potegal et al. 1983 | Predatory aggression and viewer-rated aggression directed at experimenter in isolated male rats | Microinjections (0.005–0.5 mg) of GABA receptor antagonist, muscimol, into the septum dose-dependently decreased latency to kill mice, and increased irritability (escape, biting and vocalizations). |
References | Methods and Procedures | Results and Conclusions |
Killing |
|
|
Depaulis and Vergnes 1983 | Predatory aggression in male rats | Intracerebroventricular injections of GABA receptor antagonist, bicuculline (125 ng/5 ml/rat) prolonged attack and killing latencies, and reduced percentage of animals showing mouse killing |
TABLE 5: Acctylcholine
References | Methods and Procedures | Results and Conclusions |
A. Cholinergic Correlates of Animal Aggression |
| |
Whole brain measurements |
|
|
Isolation-Induced Aggression |
|
|
Karczmar et al. 1973 | Comparison between various species of male mice. | Neural levels or turnover rates of ACh are not correlated with levels of aggression across species. |
Drug-Induced Aggression |
|
|
Jain and Barar 1986 | Clonidine-induced aggression in pairs of male and female mice. Following the aggressive interaction, mice were treated with ether and sacrificed | ACh levels in whole brain decreased following clonidine-induced fighting |
Pain-induced Aggression and Defense |
|
|
Jain and Barar 1986 | Electric foot shock in male mice. Following the aggressive interaction, mice were treated with ether and sacrificed | ACh levels in whole brain decreased following shock-induced fighting |
Peripheral correlates of aggression in animals |
|
|
Dominance-related Aggression |
|
|
Welch and Goldberg 1973 | Isolated male mice grouped in a neutral cage daily for 1–5 days. The adrenal medulla was excised 18–20 hours following the last aggressive interaction and choline acctyltransferase activity was measured | Choline acetyltransferase activity (mmol/g protein/h) was slightly decreased following 4 days of fighting experience compared to mine transferred to an empty cage. As time since the cessation of daily fighting elapsed, enzyme activity tended to increase above control values |
Stoddard et al. 1986 | Stimulation of hypothalamic sites mediating sham rage in anesthetized male and female cats. Adrenal medullary output of NE and EPI was measured. | Hypothalamic stimulation increased adrenal output of NE and EPI (ng/kg/min) |
B. Neuropharmacological Manipulations of Acetylcholine in Animals |
| |
Acetylcholinesterase Inhibitors |
|
|
Isolation-induced Aggression |
|
|
Da Vanzo et al. 1966; Herbut and Rolinski 1985; Rolinski and Herbut 1985 | Male nice tested in a neutral arena | Physostigmine (.05–1.0 mg/kg) increased aggression compared to non-injected controls. |
Pain-induced Aggression and Defense |
|
|
Anand et al. 1989 | Electric footshock in female rats | Fenitrothion, an acetylcholinesterase inhibitor, increased aggression in rats with septum, substantia nigra or amygdala lesions. Whole brain measures of NE and 5-HT were decreased in treated rats. |
Brain lesion-induced Aggression |
|
|
Stark and Henderson 1972 | Septal lesion-induced aggression in male rats | Physostigmine (.4, .57 mg/kg i.p.) decreased hyper-reactivity (target biting, irritability toward experimenter), while the peripheral anticholinesterase inhibitor, neostigmine, had no effect. Atropine (.2, .4 mg/kg i.p.) pretreatment blocked the effects of physostigmine. |
Drug-Induced Aggression |
|
|
Rolinski and Herbut 1979 | Apomorphine-induced aggression is similarly treated pairs of male rats. | Physostigmine (1 mg/kg i.p.) inhibited aggression and increased stereotypic gnawing. |
Killing |
|
|
Bandler 1969, 1970, 1971a,b | Ranacide in male rats | ACh (3–10 mg) alone had no effect but ACh with physostigmine decreased attack latencies. |
References | Methods and Procedures | Results and Conclusions |
Nicotinic Agonists |
|
|
Pain-induced Aggression and Defense |
|
|
Driscoll and Baettig 1981 | Electric footshock in male and female rats | Central or peripherally administered nicotine decreased fighting in pairs of male rats without altering vocal or escape behavior. Fighting in females only decreased at doses that also inhibited movement. |
Emley and Hutchinson 1983 | Tail-shock induced target biting in individually housed male and female squirrel monkeys | Nicotine (.32 mg/kg s.c.) elevated lever pressing while slightly decreasing target biting. |
Defensive Aggression induced by brain stimulation |
|
|
Kono et al. 1986 | ''Sham rage" in cats following electrical stimulation of the VMH | Ventral amygdalofugal but not stria terminalis lesions increased the threshold of stimulation necessary to elicit "rage." Threshold returned to control levels 48 hrs post-lesioning. ACh (.5 pmol) microinjected into the VMH increased stimulation threshold for 24 hrs in control and lesioned animals. |
Dominance-related Aggression |
|
|
Silverman 1971 | Pairs of male rats separated and re-introduced into their home cage; only one animal injected. | Nicotine (25 µg/kg s.c.) decreased aggression, social investigation and sexual behavior. |
Killing |
|
|
Bandler 1969, 1970, 1971a,b; Lonowski et al. 1973, 1975; Miczek 1976 Waldbillig 1980 | Muricide in male rats | In male rats that were muricidal, nicotine (100–1000 mg/kg i.p.) decreased muricide; central (mecamylamine 30 mg/kg) but not peripheral (hexamethonium 30 mg/kg) nicotinic receptor antagonists reversed nicotine's effects. |
Muscarinic Agonists |
|
|
Isolation-induced Aggression |
|
|
Da Vanzo et al. 1966; Herbut and Rolinski 1985; Rolinski and Herbut 1985 | Male mice tested in a neutral arena | Arecoline (.5–1.0 mg/kg), betanechol (.1–.4 mg/kg), carbachol (.05–.1 mg/kg), oxotremorine (.025–.05 mg/kg) and pilocarpine (.5–1.0 mg/kg) increased aggression compared to non-injected controls. |
Drug-Induced Aggression |
|
|
Rolinski and Herbut 1979 | Apomorphine-induced aggression in similarly treated pairs of male rats. | Pilocarpine (2.5, 10 mg/kg i.p.), oxotremorine (1 mg/kg i.p.), and choline chloride (60, 100 mg/kg i.p.) inhibited aggression and increased stereotypic gnawing. |
Hernandez-Peon et al. 1963; Baxter 1968a; Romaniuk et al. 1973; 1974; Nagy and Decsi 1979; Beleslin and Samardzic 1979; Brudzynski 1981a,b | "Sham rage" in male and female cats elicited by intracerebral drug administration | Carbachol (2.5–40 mg), or ACh (no dose stated), infused into certain regions of the diencephalon, limbic forebrain, or mesencephalon elicited "sham rage", although some reports describe defensive behavior with very little aggression. Rage was blocked either by intrahypothalamic atropine (10 mg) prior to carbachol or by the concurrent administration of carbachol (.62–1.25) into the dorsal hippocampus. Muscarine (.005–.03 mg/kg i.c.v.) resulted in attack, fear, and autonomic and motoric activation that was antagonized by atropine (.2–.5 mg/kg), scopolamine (.5 mg/kg), NE (.5–1 mg/kg), DA (.5–1 mg/kg) and EPI (.5 mg/kg). |
Killing |
|
|
Bandler 1969, 1970, 1971a,b; Lonowski et al. 1973, 1975; Miczek 1976 Waldbillig 1980 | Muricide in male rats | In muricidal rats, carbachol (2.0 mg) infused into the hypothalamus increased attack latency. Pilocarpine (12.5, 25 mg/kg/day i.p. for 3 weeks) induced muricide in 25–70% of non-muricidal rats. |
Bandler 1969, 1970, 1971a,b; Smith et al. 1970; Lonowski et al. 1973, 1975 | Muricide in female rats | In non-muricidal female rats (70%), killing was elicited by carbachol (20 mg) infused into the LH at night but not during the day. |
References | Methods and Procedures | Results and Conclusions |
Bandler 1969, 1970, 1971a,b | Ranacide in male rats | Carbachol (1–10 mg) infused into the dorsomedial thalamus or lateral hypothalamus decreased the latency to kill frogs in approximately 40% of rats. Atropine (10 mg) in the same thalamic sites blocked the facilitative effects of intrahypothalamic carbachol. Systemic atropine (10,25 mg/kg i.p.) or atropine methylnitrate (10, 25 mg/kg) also blocked carbachol's effects. Carbachol (3–10 mg) into the VTA decreased attack latencies in approximately 25% of rats. |
Berntson and Leibowitz 1973; Berntson et al. 1976 | Biting and killing of rats by male and female cats. Cats that were not spontaneously aggressive were selected. | Arecoline (5–12 mg/kg i.p.) and oxotremorine (90–150 i.p.) increased attack, hissing and growling; this effect was blocked by nicotine (.5 mg/kg) pretreatment. |
Leaf and Wnek 1978 | Male and female cats selected for spontaneous muricide | Pilocarpine (.25–.5 i.p.) decreased muricide. Methyl atropine (.125–.50 i.p.) partially blocked this effect. |
Cholinergic Antagonists |
|
|
Isolation-induced Aggression |
|
|
Herbut and Rolinski 1985; Rolinski and Herbut 1985 | Male mice tested in a neutral arena | Atropine (5.0–10.0) and scopolamine (.25–.5) suppressed aggression. Low doses of central (mecamylamine 2 mg/kg i.p.) and peripheral (hexamethonium bromide 2, 4 mg/kg i.p.) nicotine antagonists increased aggression, while higher doses decreased it. Nicotine could reverse the inhibitory effects of mecamylamine. |
Pain-induced Aggression and Defense |
|
|
Lapin 1967; Widy-Tyszkiewicz 1975 | Electric footshock in male and female mice | Atropine (.1 mM/kg i.p.), scopolamine (.1 mM/kg i.p.) and PAT-4 increased the shock threshold necessary to elicit fighting. |
Powell et. al. 1973 | Electric footshock in female rats | Atropine (10 mg/kg s.c.) and scopolamine (.25–3.0 mg/kg s.c.) decreased fighting. The peripheral antagonists, atropine methyl nitrate and scopolamine methyl nitrate, did not. |
Brain lesion-induced Aggression |
|
|
Herink et al. 1973 | Septal lesion-induced aggression in male rats | Atropine (1 mg/kg i.p.) decreased aggression in rats with septal lesions but increased aggression in controls. |
Drug-Induced Aggression |
|
|
Rolinski 1975 | PCPA-induced muricide in male and female rats | Atropine (7.5 mg/kg i.p.) and scopolamine (7.5 mg/kg i.p.) suppressed PCPA-induced muricide. |
Rolinski and Herbut 1979 | Apomorphine-induced aggression in similarly treated pairs of male rats. | Atropine (10,20 mg/kg i.p.) and scopolamine (1–4 mg/kg) suppressed aggression. |
De Feo et al. 1983 | Clonidine-induced target biting in male and female mice | Scopolamine (10–20 mg/kg p.o.) potentiated target biting and phenoxybenzamine (10–20 mg/kg p.o.) inhibited it. |
Defensive Aggression induced by brain stimulation |
|
|
Katz and Thomas 1975 | Quiet predatory aggression induced by LH stimulation | Scopolamine (1.0 mg/kg i.p.) raised the threshold of stimulation necessary to elicit attack and decreased approach and biting of attack object. |
Aggression by Resident toward intruder |
|
|
Avis and Peeke 1979 | Male convict cichlids confronted a male conspecific | Scopolamine (5 mg/l) decreased aggressive gill displays at doses that did not affect feeding or locomotion. |
Van der Poel and Remmelts 1971 | Treated male rats confronted an untreated male conspecific in a neutral environment | Scopolamine (.03–3.0 mg/kg i.p.) decreased aggressive, defensive and play behavior. Methylscopolamine (.2–30 mg/kg i.p. had no effect). |
Killing |
|
|
Smith et al. 1970; Lonowski et al. 1973; Malick 1976; Strickland and Da Vanzo 1986 | Spontaneous and olfactory bulb-induced muricide in male and female rats. | Atropine decreased spontaneous (ED50:2.9 mg/kg i.p.) and olfactory bulb-induced muricide (ED50:5.9 mg/kg i.p.). Atropine (2.5 mg) unilaterally infused into the LH had no effect on muricide. Scopolamine (1 mg/kg i.p.) also decreased spontaneous muricide. |
References | Methods and Procedures | Results and Conclusions |
C. Neuropharmacological Manipulations and Human Aggression |
| |
Experimental Studies |
|
|
Cherek 1981, 1984 | Male and female subjects: aggressive acts entailed subtracting money or administering an aversive noise to another person; non-aggressive responses earned money. | Nicotine (.42, 2.19 mg) cigarettes decreased aggressive and increased non-aggressive responding. |
Peripheral correlates of aggression in humans |
|
|
Experimental Studies |
|
|
Dotson et al. 1975 | Groups of men observed in a social setting, where alcoholic beverages, cigarettes and cigars were available ad lib. Buss-Durkee Hostility Inventory was administered immediately prior to the social interaction. | Numbers of cigarettes smoked weakly correlated (.25) with the score on the Hostility Inventory |
TABLE 6: Opioid Peptides
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
A. Opioid Correlates of Animal Aggression |
| |
Regional brain measurements |
|
|
Dominance-related Aggression |
|
|
Diaz and Asai 1990 | Group-housed mice were assigned an ordinal dominance rank. Dominance was re-determined by reassembling mice according to their initial dominance rank. Met-enkephalin was measured in brainstem and forebrain. | Met-enkephalin concentrations in the brainstem and forebrain inversely correlated with the first assessment of dominance. In the second dominance determination, dominant and subdominant also had less brainstem met-enkephalin than subordinate and non-aggressive mice; brainstem met-enkephalin concentrations decreased and increased after dominance acquisition and loss, respectively. |
CSF correlates of aggression in animals |
|
|
Dominance-related Aggression |
|
|
Martensz et al. 1986 | Group-housed male talapoin monkeys | CSF b-EP(fmol/ml) was inversely correlated with social rank: Dominant males had less b-EP than subordinate males. There was a negative correlation between the amount of aggression exhibited and the level of b-EP. Dominant males are more sensitive to the facilitatory effects of naloxone (.125–5.0 mg/kg i.m.) on plasma LH levels than intermediate and subordinate males. |
B. Neuropharmacological Manipulations of Opioid Peptides |
| |
Opioid Agonists |
|
|
Isolation-induced Aggression |
|
|
Poshivalov 1982; Benton 1985 | Male and female mice confronting a group-housed opponent | In males, met-enkephalin (50 µg i.c.v.) decreased the probability of attack and threats while increasing social investigation. Neo-endorphin (25 mg/kg i.p.) increased social investigation and locomotor behaviors. DAGO had no significant effect. In female mice, DAGO decreased social behavior and increased locomotion (250 µg, 1 mg/kg). |
Pain-induced Aggression and Defense |
|
|
Plotnikoff et al. 1976 | Electric foot shock in pairs of similarly treated male mice. | Low doses of met-enkephalin (.1, 1.0, mg/kg i.p.) decreased fighting behavior, while a higher dose (10.0 mg/kg) did not |
Tazi et al. 1983 | Electric foot shock in pairs of similarly treated male rats. | b-EP (10 mg/kg s.c.) did not affect attack rates. |
Defensive Aggression induced by brain stimulation |
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Shaikh et al. 1988, 1990 | "Sham rage" elicited by hypothalamic and periaqueductal gray stimulation in male and female cats | DAME (.25–1.0 µg/.5 µl), morphiceptin (.4 nmol), and DPDPE (.8 nmol) microinjected into the periaqueductal gray increased the threshold of stimulation needed to elicit defensive aggression. Pretreatment with naloxone (10 µg/.5 µl) blocked the suppressive effects of DAME. b-FNA and ICI 174,864 antagonized the effects of morphiceptin and DPDPE, respectively. |
Pott et al. 1987 | "Sham rage" in male and female cats elicited by stimulation of the VMH | Aggression is facilitated by concurrent stimulation of ventral central gray nuclei and inhibited by concurrent stimulation of the dorsal central gray. Naloxone (1.0 µg) microinjections antagonized the suppressive effects of dorsal central gray stimulation, but did not alter the facilitatory effects of ventral central gray stimulation |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Aggression by Resident toward Intruder |
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Christ 1985 | Male cichlids confronting a male conspecific | Low doses of met-enkephalin (10 mg/g increased fighting. High doses (30 mg/g) non-selectively decreased fighting. |
Opioid Antagonists |
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Isolation-induced Aggression |
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Poshivalov 1982; Brain et al. 1984, 1985; Benton 1985 | Male and female mice confronting a conspecific | Naloxone (.25 mg/kg i.p.) increased the frequency of attack. Detailed ethological analysis (dendrograms) indicates that naloxone (.1, 10 mg/kg s.c.) increases the association between aggressive and defensive behaviors. The delta antagonist, ICI 154,129 (30, 80 mg/kg s.c.), disrupts the normal sequence of both social and non-social behaviors, in comparison to saline-treated controls. In male but not female mice, kappa antagonists, tifluadom (.5, 1.0 mg/kg s.c.) and U-50488 (2.5, 5.0 mg/kg s.c.), decreased attack and chase while increasing defensive and non-social behaviors. |
Valenca and Falcao-Valaenca 1988 | Siamese fighting fish confronting a male conspecific | Naloxone (10 mg/l) decreased the duration of gill cover erection without altering the frequency. Avoidance measures did not differ between groups |
Pain-induced Aggression and Defense |
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Fanselow et al. 1980; Fanselow and Sigmundi 1982 | Electric foot shock in pairs of similarly treated female rats. | The number of fighting encounters increased linearly with the number of shocks administered and the shock intensity. Naloxone (4 mg/kg i.p.) increased fighting in rats receiving 1–75 shocks; naloxone enhancement of aggression was pronounced at higher shock intensities. |
Gorelick et al. 1981; McGivern et al. 1981 | Electric foot shock in isolated and group-housed male rats | Naloxone (2.5 mg/kg i.p.) pretreatment increased the duration and frequency of fighting episodes in one study, while in another it (4 mg/kg i.p.) had no effect. Naloxone injected in the middle of a session decreased fighting frequency in both isolated and group-housed rats. |
Tazi et al. 1983 | Electric foot shock in pairs of similarly treated male rats. | The incidence of fighting increased over time in rats treated with saline or naloxone (2 mg/kg s.c.) following 9 daily shock administrations; when baseline levels of fighting were low, naloxone increased the fighting episodes above saline. |
Defensive Aggression induced by brain stimulation |
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Shaikh et al. 1988, 1990 | "Sham rage" elicited by hypothalamic and periaqueductal gray stimulation in male and female cats | Naloxone (.5–10.0 mg/kg) reduced the threshold of stimulation necessary to elicit aggression. |
Aggression by Resident toward Intruder |
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Haug et al. 1986 | Castrated male mice housed in groups of 3 confronted lactating females | Naloxone (.25–2.0 mg/kg i.p.) dose-dependently decreased the frequency of attack. |
Female Aggression |
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Olivier and Mos 1986 | Maternal aggression in female rats | Naloxone (.1–12.5 i.p.) had no effect on aggression |
Dominance-related aggression |
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Meller et al. 1980 | Group-housed male talpoin monkeys | Naltrexone (500 mg/kg i.m.) decreased the frequency with which 1 of the top-ranking males attacked subordinates, but did not affect aggression in the other top-ranking male; the frequency of threats was not altered in either dominant male. Naloxone administered to subordinate males did not alter the amount of aggression received |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Reviews of the Literature |
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Animal Literature |
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Valzelli 1967 | Endocrine, anatomical and pharmacological aspects of aggression induced by brain lesion, pain, drugs, and isolation. 180 references from 1930 to 1966. | Fighting alters central catecholamine and serotonin levels and aggressive animals have a distinct drug sensitivity. Although agents from a variety of drug classes decrease fighting, none are selective for aggression. |
Rothballer 1967 | Older review of effects of hormones and neurotransmitters on aggression. 101 references | Some emphasis on role of catecholamines. |
Kermani 1969 | Neurological and biochemical data on aggression. 84 references from 1907 to 1968. | Amygdala, hypothalamus and midbrain are areas associated with hostility. NE is inversely correlated with aggressive behavior |
Bryson 1971 | Neutrotransmitter levels in environmental conditions that alter aggressive behavior. 258 references from 1877 to 1970 | NE and 5-HT levels are inversely correlated with aggression |
Welch and Welch 1971 | Relationship between neural NE, DA and 5-HT and aggression. 95 references from 1940 to 1969. | The initial effect of fighting is to elevate all 3 amines in whole brain; prolonged exposure to fighting may result in lowered amine concentrations in subcortical regions and elevations in the telencephalon |
Allikmets 1974 | Intracerebral administration of ACh, NE, DA and 5-HT and aggression in rats and cats. 75 references from 1939 to 1973 | ACh or cholinomimetics in the amygdala, septum, hippocampus, hypothalamus and mesencephalon increase aggression in cats. NE, DA and 5-HT do not. |
Johansson 1974 | Role of 5-HT, DA and NE in predatory, shock-induced, and drug-induced aggression. 33 references from 1915 to 1974. | Inhibition of 5-HT synthesis is associated with increased predatory aggression. NE is related to irritable aggression. |
Reis 1974 | Relationship between neurotransmitters and affective or predatory aggression | NE and possibly DA facilitate affective aggression and inhibit predatory aggression. ACh facilitates and 5-HT inhibits both types of aggression |
Bernard 1975 | Relationship between neural catecholamines and shock-induced aggression, ranacide and septal lesion-induced aggression. 38 references from 1956 to 1974. | Data suggest 5-HT inhibits and DA and NE facilitate aggression |
Depue and Spoont 1986 | Relationship between neural catecholamines and "irritative" aggression. 66 references from 1959 to 1986 | Irritative aggression, based in the amygdala and septum, is facilitated by DA and inhibited by 5-HT and NE |
Gianutsos and Lal 1976 | Effects of DA, NE, ACh, and 5-HT on morphine-withdrawal aggression and chemical-induced aggression. 111 references from 1953 to 1975 | DA facilitates drug-induced and morphine-withdrawal aggression. The effects of 5-HT and NE are contradictory, while the effects of ACh are unknown. |
Daruna 1978 | Relationship between brain catecholamines levels and different models of intraspecies aggression in rodents. 200 references from 1959 to 1977 | Proposes that aggressive behavior is regulated by the balance between NE and 5-HT in a few specific brain regions: Isolation-induced aggression is often facilitated by increases in DA, NE and 5-HT activity. Shock- and chemically-induced defensive aggression are correlated with increased DA, 5-HT and decreased NE or increased DA and NE and decreased 5-HT activity in mesolimbic regions |
Mandel et al. 1979 Mandel et al. 1981 | Review of 39 references on the molecular basis of aggressive behavior | GABA concentrations were lower in the olfactory bulbs of rats that displayed mouse killing behavior. Local or systemic administration of compounds that facilitate GABAergic transmission blocks mouse killing behavior, whereas compounds that inhibit GABAergic transmission induce killing behavior in non-killing rats |
| Review of 56 references on inhibitory amino acids and aggression | |
McNaughton and Mason 1980 | Reviewed the role of the dorsal ascending noradrenergic bundle in animal behavior, including various models of aggression. 542 references | Concentrations of neural NE are inversely related to aggression |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Eichelman et al. 1981; Eichelman 1986, 1987 | Review of neurochemical and pharmacological aspects of aggression and violence. 1981 review: 211 references from 1939 to 1980; 1986 review: 244 references from 1937 to 1984; 1987 review: 136 references from 1939 to 1986. | Different types of aggression depend upon the interaction of different neurotransmitters: NE and DA release correlated with increased affective aggression and decreased predatory aggression. Both types of aggression are increased by ACh activation and decreased by 5-HT release. Drugs enhancing GABA activity inhibit most types of animal aggression. |
Valzelli 1981 | Psychopharmacology of pathological aggression, as distinct from behaviors that are within a species-normal repertoire. 84 references from 1959 to 1981. | Treatment of pathological aggression should involve techniques to increase central 5-HT activity |
Pucilowski and Kostowski 1983 | 5-HT involvement in affective and predatory aggression. 110 references from 1957 to 1981 | Mesostriatal 5-HT system inhibits both affective and predatory aggression; mesolimbic 5-HT is not directly involved in either type of aggression |
Singhal and Telner 1983 | Review of 75 references on psychopharmacological aspects of aggression | GABA appears inversely related to predatory and pain-induced aggression. Increased levels of GABA inhibit shock induced fighting and predatory aggression, whereas GABA-antagonist-induced reductions in GABA produce or facilitate these types of aggression. |
Bell et al. 1985 | Review of the relationship between cholinergic drugs and neural mechanisms of affective and predatory aggression; 83 references from 1962 to 1984 | Both types of aggression are facilitated by muscarinic agents and inhibited by nicotinic agents. |
Valzelli 1985 | Neurochemical changes associated with various animal models of aggression. 28 references from 1962 to 1984. | Impaired 5-HT transmission, due to either genetic, dietary or chemical factors, is associated with aggressive behavior |
Pucilowski 1987 | Monoaminergic control of affective aggression. 140 references from 1964 to 1987 | Mesolimbic DA system facilitates affective aggression, while 5-HT and NE pathways from the locus coereleus to the amygdala and n. accumbens inhibit aggression. |
Coccaro 1989 | Review of 111 animal and human articles between 1957 and 1989 on central 5-HT and aggression | Reduction and augmentation of central 5-HT activity is related to increases and decreases in aggression, respectively |
Miczek and Donat 1989 | Neurochemical and pharmacological evidence relating 5-HT to various laboratory models of aggression. Miczek and Donat: 169 references from 1957 to 1987. Miczek et al. 1989:30 references from 1958 to 1989. | Although 5-HT systems are involved in the mediation of aggressive and defensive behaviors, there is no consistent relationship between 5-HT activity and particular types of aggressive behavior. The continuing development of 5-HT agents with specific receptor selectivity will characterize this relationship more definitively |
Human Literature |
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Verebey et al. 1978 | Clinical psychopharmacology of opiate agonists and antagonists in psychiatry. 188 references from 1972 to 1978. | There is not a great deal of supportive evidence for the use of opiate agonists or antagonists for treatment of mental disease |
Woodman 1979 | Peripheral biochemistry of patients maintained in a maximum security hospital. 36 references from 1885 to 1978 | Presents evidence for an abnormal adrenal response to stress in a subgroup of prisoners |
Eichelman et al. 1981; Eichelman 1986 | Review neurochemical and pharmacological aspects of aggression and violence. 1981 review: 211 references from 1939 to 1980; 1986 review: 244 references from 1937 to 1984; 1987 review: 136 references from 1939 to 1986. | Multiple neurotransmitter systems interact to modulate the propensity for aggressive behavior. Genetics and environmental stress can modulate the neurotransmitter systems mediating the behavior. Pharmacological treatment of aggression depends upon the etiology of the violent behavior i.e. senile dementia, sexual violence, acute schizophrenia. |
Kraemer 1985 | Relevance of CSF and peripheral measures of 5HIAA to aggressive behavior. 28 references from 1970 to 1985. | Human violence appears to be correlated with low levels of CSF 5HIAA paired with high levels of CSF NE; not clear if differences reflect etiology or indirect aspects of violent behavior. |
Muhlbauer 1985 | Role of central 5-HT in human aggression. 13 references from 1965 to 1980 | Presents data indicating a negative correlation between CSF 5HIAA and history of aggressive behavior. |
Brown and Goodwin 1986 | Relationship between suicide and aggression and CSF 5HIAA. 67 references from 1960 to 1986 | Most of the literature indicates an inverse correlation between CSF 5HIAA and aggression, alcoholism and suicide |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
van Praag et al. 1986 van Praag et al. 1987 | Relationship between 5-HT and psychopathology. 1986:65 references from 1950 to 1985. 1987:74 references from 1965 to 1987 | Low CSF 5HIAA correlate with various measures of hostility and aggression |
Roy et al. 1987 | CSF 5-HT turnover and violence in a subgroup of alcoholics. 29 references from 1973 to 1986 | Low CSF 5HIAA correlated with suicidal and impulsive behavior in alcoholics. |
Burrowes et al. 1988 | Neurochemical and other physiological correlates of violence. 70 references from 1969 to 1987 | CSF 5HIAA levels inversely correlate with psychological tests of aggression or irritability |
Roy and Linnoila 1988 | Relationship between violent and suicidal behavior and 5-HT. 14 references from 1976 to 1987. | CSF 5HIAA is inversely correlated with aggression, alcoholism and suicide. |
Coccaro 1989 | Review of 111 human and animal articles between 1957 and 1989 on central 5-HT and aggression | Central 5-HT activity is reduced in mood and personality disorder patients with history of suicidal and/or impulsive aggressive behavior |
Ellis 1991 | Review of 173 articles on the relationship between MAO and antisocial behavior | Correlates low platelet MAO activity with high probability of criminality, psychopathy and drug abuse; no evidence of a causal relationship presented. |
TABLE 7A: Effects of Antipsychotics on Aggression in Animals
References | Methods and Procedures | Results and Conclusions |
Isolation-Induced Aggression |
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Yen et al. 1959 | Male albino mice, individually housed for 3 weeks; 5 min. observation | Chlorpromazine (10 mg/kg, p.o.) decreased both aggressive and motor activities. |
Cook and Weidley 1960 | Mice, individually-housed for at least 25 days, paired with non-isolated intruder | Chlorpromazine: ED50 for inhibiting attack behavior=11.3 mg/kg p.o.; prochlorperazine: ED50=7.4 mg/kg; trifluoperazine: ED59=5.4 mg/kg; trimeprazine: ED50=9.5 mg/kg; methiomeprazine: ED50=7.0 mg/kg. |
Janssen et al. 1960 | Male mice, individually-housed for 24 hours; 1 min. observation | Acetopromazine (ED50=1 umol/kg), triflupromazine (ED50=2.8 umol/kg), methopromazine (ED50=2.9 umol/kg), chlorpromazine (ED50=3.1 umol/kg), promazine (ED50=16 umol/kg), perphenazine (ED50=1.6 umol/kg), thiopropazate (ED50=2.1 umol/kg), prochlorperazine (ED50=7.8 umol/kg), and haloperidol (ED50=1.9 umol/kg) decreased aggression only at doses which suppressed locomotor activity. |
Gray et al. 1961 | Male albino mice, individually-housed; 3 min observation | Chlorpromazine (ED50=8 mg/kg) non-selectively decreased aggressive behavior. |
Scriabine and Blake 1962 | Male albino mice, selected for aggressive behavior and isolated for 24 hr; tested in pairs, 5 min observation | Chlorpromazine (0.5 mg/kg i.p.) decreased fighting time; impairment of motor activity was observed with 4–8 mg/kg. |
Cole and Wolf 1966 | Male and female mice, individually-housed for 3 days-3 weeks; 5 min. observation | Chlorpromazine (5 mg/kg i.p.) decreased fighting in one strain of the 2 tested (Onychomys torridus) and increased latency to attack; these animals also appeared sedated. |
Da Vanzo et al. 1966 | Male C57 B1/10J or Dublin (ICR) mice, individually- or group-housed for 3 weeks; 3 min. observation | Chlorpromazine: ED50 for reducing aggressive behavior=1.54 mg/kg i.p.; perphenazine: ED50=1.84 mg/kg i.p.; butaperazine: ED50=6.7 mg/kg (C57 B1/10J mice) and 8.5 mg/kg (Dublin mice). |
Valzelli et al. 1967 | Male Swiss albino mice, individually housed for 4 weeks; tested in groups of 3 for 5 min.; 5-point rating scale for aggressive behavior | Chlorpromazine (2.5, 10 mg/kg, i.p.), levomepromazine (0.3–1.2 mg/kg) and propericiazine (0.5, 1 mg/kg) decreased aggressive behavior, 10 mg/kg chlorpromazine produced overt sedation. |
Boissier et al. 1968 | Male CF1 mice, isolated 24–48 hours; 5 min. observation | Chlorpromazine (1–8 mg/kg p.o) and haloperidol (.125–.5 mg/kg p.o.) dose-dependently decreased aggressiveness. |
Hoffmeister and Wuttke 1969 | Mice, individually-housed for several days; tested with non-isolated intruder | Chlorpromazine: ED50 for inhibition of aggression=93.23 mg/kg p.o.; ED50 for sedation=33.05 mg/kg |
Le Douarec and Broussy 1969 | Male and female CD and Swiss mice, individually-housed for 1 month; 5 min. observation, both animals in test drugged | Chlorpromazine (2 mg/kg) significantly reduced attacks by isolated mouse and vocalizations by intruder without affecting motor behavior; 4 mg/kg chlorpromazine decreased motor behavior with aggressiveness. |
Sofia 1969b | Male Swiss Webster mice, individually-housed for 8 weeks; 3 min observation; rotarod test for neurotoxicity | Chlorpromazine (ED50=1.6 mg/kg), methotrimeprazine (ED50=3.0 mg/kg), thioridazine (ED50=4.6 mg/kg) and thiothixene (ED50=50 mg/kg) non-selectively decreased aggressive behavior. |
Cole and Wolf 1970 | Male and female mice (Onychomys leucogaster and O. torridus), individually housed for 3 days-3 weeks; 5 min observation | Chlordiazepoxide (O. leucogaster: 5.0 mg/kg, O. torridus: 5.1 mg/kg) significantly increased mean fighting time of mice; chlorpromazine (O. leucogaster: 27 mg/kg, O. torridus: 14.75 mg/kg) decreased fighting time in O. torridus. |
References | Methods and Procedures | Results and Conclusions |
Valzelli 1971 Valzelli and Bernasconi 1976 | Male mice, individually housed for 4 weeks; tested in groups of 3; exploration measured using a hole board. | Chlorpromazine (5 mg/kg i.p.), propericiazine (1 mg/kg), haloperidol (1 mg/kg) and properciazine (1 mg/kg) decreased fighting; properciazine (0.1 mg/kg i.p.) decreased exploratory behavior of normal mice but not of aggressive mice. |
Cairns and Scholz 1973 | Male mice, individually- or group-housed for 7 weeks; 10 min. observation; non-isolated intruder was drugged | Chlorpromazine (4–16 mg/kg i.p.) administered to intruder decreased attacks by isolated mouse due to decreased reactivity of intruder. |
Goldberg et al. 1973 | Male and female mice, individually-house for 5 weeks; 1 min. observation | Chlorpromazine (1.25–5 mg/kg i.p.) inhibited fighting behavior in males at doses which caused 60% inhibition in motor activity; isolated females did not become aggressive; CPZ inhibits 5-HT synthesis in isolated males. |
Maengwyn-Davies et al. 1973 | Male BALB/C, A/He J and C57BR/edJ mice, individually or group-housed for 2 weeks; aggressiveness toward another male measured for 10 minutes daily for 7 consecutive days | C57BR/edJ mice did not become aggressive after isolation; in these mice, chlorpromazine (4 mg/kg s.c.) did not alter defensive behavior; chlorpromazine did not affect the elevated adrenal tyrosine hydroxylase activity and was minimally effective in altering elevated phenylethanolamineN-methyltransferase in response to fighting stress. |
Poshivalov 1973 | Mice, individually-housed or 1–012 weeks | Droperidol (0.125–1.25 mg/kg) decreased fighting. |
Barnett et al. 1974 | Male CF-1 mice, individually-housed; tested in home cage; 3 min observation | Benzazepine (SCH 12679, ED50=14.6 mg/kg i.p.) selectively decreased fighting. Perphenazine (ED50=1 mg/kg i.p.) nonselectively decreased fighting. |
Niemegeers et al. 1974 | Male mice, individually-housed; 1 min. observation | Azaperone (.31–2.5 mg/kg, ED50=.74 mg/kg) dose-dependently inhibited fighting at doses 10 times lower than doses producing loss of righting reflex (ED50=7 mg/kg); azaperone is more selective in inhibiting aggression than haloperidol, levomepromazine, promazine or chlorpromazine. |
Poshivalov 1974 | Male C57BL mice, individually-housed for 1 day-12 weeks; 5 min. observation | Haloperidol (.06 mg/kg i.p.) decreased aggression without influencing motor behavior, higher doses of haloperidol (.125, 1.25 mg/kg) and chlorpromazine (1, 5 mg/kg i.p.) decreased motor behavior along with aggression. |
Coscina et al. 1975 | Male Swiss mice, individually-housed or 4 weeks; tested in groups of 9 | Chlorpromazine: ED50 for reducing aggression=1.92 (1 hr.), ED50 for reducing spontaneous motor activity=8.1 mg/kg; piperazine derivatives RMI 61 140, RMI 61 144, RMI 61 280: ED50 for reducing aggression=.05-.11 mg/kg, ED50 for reducing motor activity=.25-.37 mg/kg. |
Hodge and Butcher 1975 | Male mice, individually-housed; latency, frequency, and duration of fighting measured; 15 min. observation. | Pimozide (0.1–0.8 mg/kg i.p.) decreased frequency of fighting and locomotor activity; disulfiram (45–190 mg/kg i.p.) decreased fight frequency and duration, increased latency to attack and decreased locomotor activity. |
Kršiak 1975a,b | Male ''timid" and aggressive mice, individually-housed for 3–6 weeks; tested with group-housed males in a neutral cage | Chlorpromazine (7.5 mg/kg) inhibited timidity without affecting motor activities; 2.5 mg/kg chlorpromazine selectively decreased tail rattling in aggressive mice. |
Rolinski 1975 | Male Swiss mice, individually-housed for 4 weeks; tested in pairs with another isolate; 5 min. observation | Pimozide, alpha-methyltyrosine, spiramide, trifluperazine and haloperidol all reduced aggression at doses higher than the ED50 for reducing motor activity; only phenoxybenzamine reduced aggression at doses lower than the ED50 for reducing motor activity. |
References | Methods and Procedures | Results and Conclusions |
Tobe and Kobayashi 1976 | Male ddY mice, individually-housed for 6–7 weeks; tested in pairs, 10 min. observation | Chlorpromazine: ED50 for suppresing aggression=3.9 mg/kg p.o., 1.7 mg/kg i.p., ED50 for suppressing motor activity=6.8 mg/kg p.o., 2.0 mg/kg i.p.; TR-10 (a triazine derivative): ED50 for suppressing aggression=18 mg/kg p.o., 9.0 mg/kg i.p., ED50 for suppressing motor activity=13.5 mg/kg p.o., 12 mg/kg i.p. |
Humber et al. 1979 Philipp et al. 1979 | Male mice, individually-housed 4–5 weeks; 5 min. observation | Butaclamol inhibited fighting (ED50=1.9 mg/kg i.p.) and caused some catalepsy; the butaclamol analogues anhydrobutaclamol and deoxybutaclamol inhibited fighting behavior (ED50s=3.0 and 2.1 mg/kg) but only at doses which induce 100% catalepsy; isobutaclamol inhibits fighting (ED50=2 mg/kg) at a dose which induces some catalepsy (45% of max). |
Olivier and van Dalen 1982 | Male mice, individually-housed for 3 weeks, tested in a neutral cage with a group-housed intruder for 5 min. | Chlorpromazine (2.5, 5 mg/kg) non-specifically decreased aggressive behavior. |
Poshivalov 1982 | Male CC57W mice, individually-housed for 6–8 weeks; tested weekly with group-housed intruder for 4 min. | Haloperidol (1 mg/kg) decreased attack frequency, sociability and locomotion. |
Benton 1984 | Male TO mice, individually- or group housed for 4–5 weeks; 23 hr. automated observation | Chlorpromazine (1–5 mg/kg s.c.) dose-dependently decreased aggression as measured by squeaking. |
McMillen et al. 1989 | Male mice, individually-housed for 3 weeks; 3 min. observations, measured fight frequency and locomotor activity | Inhibition of aggression by clozapine (1–5.5 mg/kg), sulpiride (3–30 mg/kg), haloperidol (.01–1 mg/kg), SCH 23390 (.01–1 mg/kg) and trifluoperazine (1, 3 mg/kg) is secondary to inhibition of locomotor activity; Chlorpromazine (3 mg/kg) inhibited fighting with less disruption of locomotor activity; BMY 20661 (ED50=.46 mg/kg) did inhibit aggression without disrupting locomotor activity. |
Redolat et al. 1991 | Male albino mice, isolated 5–6 weeks; tested with group-housed anosmic (zinc sulfate) opponents; 10 min observation. | Acute sulpiride (20, 50, 100 mg/kg i.p.) dose-dependently decreased attacks and threats, while increasing both immobility and non-social exploration. Chronic treatment (10, 20, 50 mg/kg sulpiride for 1 or 2 weeks) only increased immobility. |
Pain-Induced Aggression and defense |
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In Mice |
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Tedeschi et al. 1959b | Male CF-1 mice, tested in pairs while receiving footshock; 3 min observation | Chlorpromazine (ED50=6.8 mg/kg p.o.), prochlorperazine (ED50=4.6 mg/kg) and trifluoperazine (ED50=0.85 mg/kg) decreased fighting only at sedative doses. |
Chen et al. 1963 | Male Swiss Webster mice, tested in pairs after receiving foot shock | Chlorpromazine (ED50=4.2 mg/kg p.o.) decreased fighting (sedative effects not tested). |
Kostowski 1966 | Mice, tested in pairs while receiving foot shock; 3 min observation | Chlorpromazine (5 mg/kg i.p.) decreased aggressiveness and induced ataxia. |
Hoffmeister and Wuttke 1969 | Male mice, tested in pairs while receiving electric foot shock | Chlorpromazine: ED50 for inhibition of aggressive behavior=9.99 mg/kg p.o. |
Sharma et al. 1969 | Mice, tested in pairs while receiving mild intermittent electric foot shock, 1 min. observation | Chlorpromazine (3–10 mg/kg), phenocyloxime chlorpromazine (5, 10 mg), trifluoperazine (3–10 mg/kg), diphenacyloxime trifluoperazine (5, 10 mg/kg), perphenazine (1–10 mg/kg) and diphenacyloxime perphenazine (5, 10 mg/kg) dose-dependently suppressed fighting; these doses also significantly decreased motor activity. |
Sofia 1969b | Mice, tested in pairs while receiving foot shock; 3 min observation; Rotarod test for neurotoxicity | Chlorpromazine (ED50=3.4 mg/kg), methotrimeprazine (ED50=2.6 mg/kg) and thiothixene (ED50=33.4 mg/kg) non-selectively decreased aggressive behavior; thioridazine (ED50=4.8 mg/kg) selectively decreased aggressive behavior. |
References | Methods and Procedures | Results and Conclusions |
Tedeschi et al. 1969 | Mice, tested in pairs while receiving foot shock; 3 min observation | Chlorpromazine (ED50=10.8 mg/kg p.o.), promazine (ED50=16 mg/kg), prochlorperazine (ED50=5.1 mg/kg), trifluoperazine (ED50=1.8 mg/kg), perphenazine (ED50=2.5 mg/kg), thioridazine (ED50=18.7 mg/kg), and chlorprothixene (ED50=4.3 mg/kg) decreased fighting at doses which also decreased locomotor activity. |
Barkov 1973 | Mice, tested in pairs while receiving foot shock | Chlorpromazine: ED50 for suppression of aggression=1.1 mg/kg, carbidine: ED50=0.039 mg/kg. |
Shintomi 1975 | Male ddY mice, tested in pairs while receiving foot shock | Haloperidol (ED50=8.3 mg/kg p.o.), trifluperidol (ED50=8.3 mg/kg), benperidol (ED50=15.7 mg/kg), spiroperidol (ED50=12.4 mg/kg), chlorpromazine (ED50=15.7 mg/kg), trifluopromazine (ED50=8.3 mg/kg), levomepromazine (ED50=8.3 mg/kg), perphenazine (ED50=12.4 mg/kg), prochlorperazine (ED50=24.6 mg/kg), trifluoperazine (ED50=8.3 mg/kg), thioridazine (ED50=40.8 mg/kg), thiothixene (ED50=12.4 mg/kg), chlorprothixene (ED50=18.5 mg/kg), clothiapine (ED50=12.4 mg/kg) and mepazine (ED50=82.6 mg/kg) antagonized shock-induced fighting and hyperactivity. |
Rolinski and Kozak 1979 | Male mice, tested in pairs while receiving foot shock; also tested spontaneous motor activity | Haloperidol (0.5, 1 mg/kg i.p.) and pimozide (1 mg/kg) significantly decreased aggressive behavior at doses higher than ED50 for causing immobility. |
Nakao et al. 1985 | Male ddY mice, tested in pairs while receiving foot shock | Haloperidol (0.5 mg/kg i.p.) significantly decreased the number of fighting episodes. |
In Rats |
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Brunaud and Siou 1959 | Male rats, tested in pairs while receiving foot shock | Chlorpromazine (5 mg/kg) reduced aggressive behavior without sedative effects. |
Laverty and Taylor 1969 | Male rats, tested in pairs while receiving foot shock | Chlorpromazine (1–5 mg/kg s.c.) dose-dependently reduced fighting, rotarod time and motor activity. |
Barkov 1973 | Rats, tested in pairs while receiving foot shock | Chlorpromazine: ED50 for suppression of aggression=3.5 mg/kg, carbidine: ED50=0.22 mg/kg. |
Powell et al. 1973 | Male and female Sprague-Dawley rats, pair-housed, tested in same-sex pairs while receiving foot shock | Chlorpromazine (0.5–10 mg/kg s.c.) dose-dependently decreased fighting. |
Lal et al. 1975 | Male rats, tested in pairs while receiving foot shock | Haloperidol (0.63 mg/kg) reduced aggression at each shock intensity level. |
Rodgers et al. 1976 | Male Sprague-Dawley rats, tested in pairs while receiving foot shock | Chlorpromazine and haloperidol (10 ug i.c. to corticomedial amygdala) reduced both fighting and pain sensitivity. |
Bean et al. 1978 | Male Long-Evans rats, tested in pairs while receiving foot shock | Benzazepine (2.5–20 mg/kg i.p.) dose-dependently reduced fighting, time on rotarod and spontaneous motor activity. |
Hegstrand and Eichelman 1983 | Male Sprague-Dawley rats, tested in pairs while receiving foot shock | Haloperidol (1 mg/kg/day, i.p., 14 days) significantly decreased number of attacks; DA receptor density increased 37% in caudate. |
In Squirrel Monkeys |
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Emley and Hutchinson 1972 Emley and Hutchinson 1983 | Male and female squirrel monkeys, lever pressing responses and biting responses on a latex rubber hose were measured while shock delivered to tail | Chlorpromazine (.06–2 mg/kg s.c.) dose-dependently decreased biting; low doses increased and higher doses decreased lever-pressing in response to shock. |
Experimenter-Provoked Aggression |
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In cats |
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Hoffmeister and Wuttke 1969 | Cats, provoked into displaying defensive-aggressive behavior using a leather glove | Chlorpromazine (2.5–10 mg/kg p.o.) inhibited aggressive behavior. |
References | Methods and Procedures | Results and Conclusions |
In monkeys |
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Das et al. 1954 | Spontaneously aggressive rhesus monkeys | Chlorpromazine (0.7–2 mg/kg) eliminated aggressive behavior and produced akinesia and somnolence in 8 of the animals; 1 monkey which was previously timid became aggressive. |
Barkov 1973 | Spontaneously aggressive male monkeys (rhesus, green guenon) | Trifluoperazine (5–10 mg/kg) and carbidine (4–14 mg/kg) reduced aggressiveness, higher doses caused sedation: chlorpromazine (3, 10 mg/kg) and perphenazine (5–10 mg/kg) chiefly caused sedation without affecting aggressiveness. |
Barnett et al. 1974 | Rhesus monkeys, selected for aggressive behavior toward investigator. | Benzazepine (SCH 12679, 1.25–10 mg/kg s.c.) dose-dependently decreased aggressive behavior without producing motor impairment; perphenazine (0.25 mg/kg s.c.) non-selectively decreased aggression. |
Defensive aggression induced by brain stimulation |
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Kido et al. 1967 | Male and female cats; electrical stimulation applied to posterior hypothalamus and central gray. | Chlorpromazine (3 mg/kg i.v.) decreased rage response induced by stimulation of posterior hypothalamus and hissing induced by stimulation of central gray. |
Baxter 1968b | Male and female cats; electrical stimulation applied to perifornical region of hypothalamus | Chlorpromazine (1–5 mg/kg i.p.) had inconsistent effects on hissing threshold; 5 mg/kg produced depression and ataxia. |
Funderburk et al. 1970 | Male and female cats; electrical stimulation applied to perifornical region of hypothalamus; hissing response measured | Chlorpromazine (2.5 mg/kg) and triperidol (2.5 mg/kg) lowered the threshold for hissing; trifluoperazine and perphenazine (1, 2 mg/kg) increased the threshold for hissing. |
Dubinsky and Goldberg 1971 | Male and female cats, electrical stimulation to the perifornical region of the hypothalamus, the ventral hippocampus and the dorsal medial nucleus of the thalamus | Chlorpromazine (2–8 mg/kg) did not suppress rat killing despite severe locomotor deficits. |
Malick et al. 1969 | Male Long-Evans rats with bilateral septal, olfactory bulb and ventral medial hypothalamus lesions; tested for responses to inanimate objects | Chlorpromazine: ED50 for inhibiting aggression=12.1 mg/kg i.p. (septal), 22.7 mg/kg (VMH), 5.9 mg/kg (OB); trifluoperazine: ED50 for inhibiting aggression=11.5 mg/kg i.p. (septal), 18.4 mg/kg (VMH), 6.7 mg/kg (OB). |
Goldberg 1970 | Male Long-Evans rats, received bilateral electrolytic septal lesions; tested for aggressive reactions to an inanimate object; rotarod test for neurotoxicity | Chlorpromazine (ED50=11.3 mg/kg i.p.) decreased aggression at doses causing neurotoxicity. |
Ueki et al. 1972 | Male rats, individually housed, received olfactory bulbectomies or electrolytic lesioning of the septum or amygdala; selected for "emotionality" and mouse-killing | Chlorpromazine (5, 10 mg/kg i.p.) decreased muricide, attack response to an inanimate object, and motor activity in olfactory bulbectomized and septal rats. |
Barnett et al. 1974 | Male Long-Evans rats, received electrolytic lesions to septum; tested for aggressiveness to inanimate object | Benzazepine (SCH 12679, ED50=22.2 mg/kg i.p.) selectively decreased aggressive behavior; perphenazine (ED50=4.5 mg/kg i.p.) non-selectively decreased aggression. |
Aggression due to omission of reward |
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In Rats |
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Thompson 1961, 1962 | Male rats, water deprived; trained to lever press for water reinforcement which was later withheld; aggression defined as marked increases in lever responding | Chlorpromazine (1.5 mg/kg, i.p., 4 times daily for 4 days) increased "aggressive" lever responding during the extinction period. Chlorpromazine (0.9–3.0 mg/kg, i.p.) and thioridazine (3.0–11.5 mg/kg, i.p.) increased "aggressive" responding at low doses and decreased ''aggressive" responding at higher doses. |
References | Methods and Procedures | Results and Conclusions |
Andy and Velamati 1978 | Male cats; electrical stimulation to the septum, hypothalamus, amygdala, preoptic area, basal ganglia and hippocampus | Haloperidol and phenoxybenzamine reduced the production of aggressive seizures but also lowered the threshold for evoking stimulus-bound aggression. |
Fukuda and Tsumagari 1983 | Male and female cats; electrical stimulation to medial hypothalamus; measured hissing and attack toward experimenter | Chlorpromazine (ED50=5 mg/kg) increased the threshold for directed attack at doses which caused sedation; haloperidol (1 mg/kg) and chlorpromazine (1 mg/kg) did not change the hissing threshold. |
Sweidan et al. 1990 | Male and female cats; electrical stimulation to ventromedial hypothalamus; defensive behavior facilitated with apomorphine (0.1–1 mg/kg i.p.); measured hissing threshold | Pretreatment with haloperidol (0.1, 0.5 mg/kg i.p.), spiperone (0.2 mg/kg) and SCH 23390 (0.5 mg/kg) antagonized facilitatory effect of apomorphine on hissing. In cats not receiving apomorphine, haloperidol (0.1 mg/kg), spiperone (0.2 mg/kg) and SCH 23390 (0.1 mg/kg) suppressed hissing. |
Brain lesion-induced irritability |
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In Mice |
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Kletzkin 1969 | Male mice, individually- or group-housed, received septal lesions; tested for aggressive reactions to inanimate objects and fighting with an untreated mouse | Chlorpromazine (2 mg/kg i.p.) abolished fighting in normal, septal, and isolated mice without altering reactivity. |
In Rats |
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Horovitz et al. 1963 | Rats with bilateral septal lesions; tested for reaction to an inanimate object; rotarod test for neurotoxicity | Chlorpromazine (ED50=6.8 mg/kg i.p.) decreased irritability at sedative doses. |
Beattie et al. 1969 | Male Wistar rats with septal and/or hypothalamic electrolytic lesions; reactivity to handling stress was rated | Chlorpromazine (ED50=1.25 mg/kg) produced "taming" without causing neurological deficits in rats with septal lesions; in rats with hypothalamic or hypothalamic-septal lesions chlorpromazine produced taming (ED50=2.5 mg/kg) with minimal neurological deficits. |
Drug-induced aggression |
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In Mice |
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Yen et al. 1970 | Male ICR mice, injected with 500 mg/kg l-DOPA i.v. to induce aggression; biting response to an inanimate object measured | Chlorpromazine: ED50 to reduce aggression=2.4 mg/kg i.p., TI=49, haloperidol: ED50=0.9 mg/kg, TI=47, reserpine: ED50=0.18 mg/kg, TI=389, trifluoperazine: ED50=0.15, TI=1233. |
Hasselager et al. 1972 | Male NMRI mice, injected with d-amphetamine to induce aggression; measured agonistic behavior among groups of 4 mice housed under highly crowded conditions every other minute for 180 minutes after injection | Spiramide (0.5–1 mg/kg) and trifluperazine (0.15 mg/kg) inhibited aggressive behavior without causing sedation. |
Rolinski 1973, 1974 | Swiss mice, treated with amphetamine (15 mg/kg s.c.) and/or l-DOPA (200 or 800 mg/kg i.p.) to induce aggression; tested in groups of 4 | Pimozide (0.125, 0.25 mg/kg i.p.), spiramide (0.1, 1.2 mg/kg), trifluperazine (0.15 mg/kg) and nialamide (40 mg/kg) pretreatment selectively reduced aggressive behavior induced by amphetamine or l-DOPA; FLA 63 (30 mg/kg) had no effect. |
Lal et al. 1975 | Mice, treated with 4 mg/kg amphetamine and 400 mg/kg dl-DOPA to induce aggression, tested in groups | Haloperidol (1 mg/kg) inhibited attacks, defensive rearing and vocalizations. |
In Rats |
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Lammers and Van Rossum 1968 | Male Wistar rats, treated with Ro 4-4602 (52.3 mg/kg i.p.) and amphetamine (.54–1.72 mg/kg i.p.) or l-DOPA (6.23–62.3 mg/kg i.p.) to induce aggression; tested in groups of 6 | Chlorpromazine (3.55 mg/kg i.p.) and haloperidol (0.4 mg/kg i.p.) suppressed defensive rearing. |
Nakamura and Thoenen 1972 | Male Wistar rats; aggression induced with i.v. injection of 6-OHDA; measured responses (irritability) to non-painful stimuli | Chlorpromazine (ED50=5.09 mg/kg i.p.) and haloperidol (ED50=0.72 mg/kg i.p.) decreased irritability only at doses which caused catalepsy. |
Gianutsos et al. 1974 | Male Long-Evans rats, treated chronically with haloperidol (2.5–20 mg/kg/day i.p. for 16 days); tested in groups, 60 min. observation | Chronic haloperidol induced catalepsy; haloperidol withdrawal induced "wet dog shakes" and intense aggression in response to a sub-threshold dose of apomorphine. |
References | Methods and Procedures | Results and Conclusions |
Lal et al. 1975 | Male rats; aggression elicited with apomorphine (20 mg/kg) or by withdrawal from morphine | Haloperidol (0.63, 2.5 mg/kg) reduced attacks, defensive rearing, and vocalizations in apormorphine-treated and morphine withdrawn animals. |
Shintomi 1975 | Male ddK mice, group-housed; aggression elicited with methamphetamine (5 mg/kg s.c.) | Haloperidol (0.1, 0.5 mg/kg p.o.), trifluperidol (0.1, 0.5 mg/kg), benperidol (0.25, 0.5 mg/kg), spiroperidol (0.1, 0.25), chlorpromazine (5, 10 mg/kg), trifluopromazine (0.5, 1 mg/kg), levomepromazine (1 mg/kg), perphenazine (1 mg/kg), prochlorperazine (1, 2.5 mg/kg), trifluoperazine (0.5, 1 mg/kg), thioridazine (5, 10 mg/kg), thiothixene (1, 5 mg/kg), chlorprothixene (2.5–10 mg/kg), clothiapine (1 mg/kg) and mepazine (200 mg/kg) antagonized methamphetamine-induced fighting and hyperactivity. |
Zetler and Hauer 1975 | Male Wistar rats, housed in groups of 5; aggression induced by combined injection of isocarboxazid (MAO inhibitor) and imipramine; tested response to inanimate object | Chlorpromazine (1–5 mg/kg i.p.), trifluoperazine (0.15–5 mg/kg), acepromazine (1.5–5 mg/kg), and propionylpromazine (1.25–10 mg/kg) decreased biting at doses which induced catalepsy; haloperidol (5 mg/kg) decreased biting without inducing catalepsy. |
Albert and Richmond 1977 | Male hooded rats; tested for reactivity to presentation of pencil or gloved hand, or to prodding or grasping of the body (3-point scale) after injection of dopaminergic, alpha-adrenergic, beta-andrenergic, and cholinergic antagonists injected i.c. ventral to anterior septum | Haloperidol (5 mg/ml) did not increase reactivity over saline control levels. |
Mueller et al. 1982 | Male Long-Evans rats, treated with caffeine (140 mg/kg s.c.) or amphetamine (43 mg pellet implanted s.c. for 4.5 days+3 mg/kg i.p.) to induce self-injurious behavior (SB) | Haloperidol (0.2 mg/kg i.p.) pretreatment did not significantly reduce SB in caffeine-treated animals; pimozide (1.5 mg/kg i.p.) pretreatment eliminated SB in amphetamine-treated animals. |
Pucilowski and Kostowski 1988 | Male Wistar rats; aggression induced by apomorphine injection; 5 min. observation of aggression among paired rats | Rats which were originally non-responsive to apomorphine exhibited aggression after ethanol or haloperidol withdrawal (14 days, 0.5 mg/kg twice daily); co-administration with diltiazem decreased this aggression. |
In chicks |
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Ayitey-Smith and Addae-Mensah 1983 | Male and female chicks, treated with apomorphine (0.5 mg/kg s.c.) to induce aggression; tested in pairs | Chlorpromazine (10 mg/kg i.p.) pretreatment completely antagonized aggressive behavior to self and other chicks but did not abolish pecking to inanimate objects. |
Aggression by resident toward intruder |
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In mice |
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Kršiak and Steinberg 1969 | Male TO mice, residents housed in groups of 4 and intruders individually-housed; all residents in group drug-treated; 6 min observation | Chlorpromazine (4 mg/kg, i.p.) decreased aggression and induced sedation. |
Thurmond 1975 | CF-1 mice, housed individually for 24 hours; tested with an intruder male; 30 min. observation | Chlorpromazine (2.5 mg/kg, i.p.) decreased the number of residents attacking, decreased number of attacks and increased latency to attack. |
Dixon 1982 | Male LAC mice, individually-housed for 4 weeks; tested with group-housed male intruders (intruder received drug); 6 min observation | Clozapine (0.3–1 mg/kg p.o.) selectively increased defensive behavior. |
In rats |
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Silverman 1965a,b, 1972 | Male rats, individually housed, tested in pairs in home cage of drugged rat, 10 min. observation | Chlorpromazine (1, 4 mg/kg, i.p.) reduced aggression by reducing responsiveness to external stimuli. |
Olivier and van Dalen 1982 | Male rats, tested in home cage with male intruder | Haloperidol (0.04–0.2 mg/kg) non-specifically decreased aggressive behavior. |
References | Methods and Procedures | Results and Conclusions |
Female aggression |
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Yoshimura and Ogawa 1989 | Female ICR mice, housed with a male for 4 days and then housed alone; tested with male group-housed intruders on postpartum days 5 and 7; 5 min observation | Haloperidol (0.1–0.4 mg/kg i.p.) dose-dependently decreased biting and locomotion; chronic haloperidol (0.1, 0.2 mg/kg for 20–22 days) did not significantly after biting or locomotion. |
Dominance-related aggression |
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In fish |
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Walaszek and Abood 1956 | Male Siamese fighting fish, individually housed; tested for aggressive responses to conspecifics | Chlorpromazine (2 ug per milliliter tank water) caused sedation and eliminated aggression. Chlorpromazine sulfoxide (50 ug per milliliter tank water) had no effect. |
Munro 1986 | Female blue acaras, individually-housed; tested for aggressive responses to mirrors or models | Chlorpromazine (2.5–20 mg/10 l tank water) decreased incidence of biting and decreased displays (approach/avoidance behavior) at higher doses; motor activity was decreased. |
In mice |
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Vessey 1967 | Male and female mice (Mus musculus, C57) of three confined, freely-growing populations; 20 min. observation | Aggressive interactions increased with increases in populations size; chlorpromazine (>0.6 mg/g food) reduced aggressive behavior and increased infant survival. |
Zwirner et al. 1975 | Male OF-1 mice, housed in groups of 3; 10 min observation; tested aggressive behavior between 2 groups | Chlorpromazine (1–10 mg/kg p.o.) decreased aggression at doses which also decreased locomotor activity. |
In rats |
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Heimstra 1961 | Male Wistar rats, individually housed, 22 hr. food-deprived; tested in pairs, 5 min. observation | Chlorpromazine (0.5 mg/kg i.p.), when administered to either the dominant or the submissive animal caused that animal to gain control of the food source; administration of chlorpromazine to one or both animals reduced fighting behavior. |
In cats |
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Hoffmeister and Wuttke 1969 | Male cats, tested for aggressive behavior toward an untreated male cat; 6-point aggression score | Chlorpromazine (2.5–8 mg/kg p.o.) abolished attack behavior. |
In pigs |
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Gonyou et al. 1988 | Pigs, tested in groups of 15; 48 hour observation | Both amperozide (1 mg/kg i.m.) and azaperone (2.2 mg/kg i.m.) decreased overall aggressiveness of group; amperozide was more selective. |
In monkeys |
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Lister et al. 1971 | Social colony of baboons | Chlorpromazine (2.5 mg/kg i.m.), administered to the dominant male, reduced aggressive behavior by about 50%, 3 mg/kg was sedative. |
Miczek and Yoshimura 1982 | Male squirrel monkeys, housed in social colonies, treated with d-amphetamine (1 mg/kg p.o.) or cocaine (10 mg/kg p.o) to induce altered social behavior | Chlorpromazine (0.25–1 mg/kg p.o.) and haloperidol (0.25, 0.5 mg/kg p.o.) pretreatment antagonized locomotor effects of amphetamine and cocaine but did not reliably normalize social behavior. |
Killing |
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In mice |
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Gay and Clark 1976 | Male Onychomys leucogaster (northern grasshopper mice), induced to kill CBA mice with electric shock | Chlorpromazine (2.5, 5 mg/kg i.p.) did not alter killing but facilitated killing on postdrug trials. |
Poshivalov 1980 | Male CC57W mice, selected for aggressive behavior and rated for dominant status | Droperidol (2.5 mg/kg) inhibited aggression, sociability and locomotion; chronic administration (7 days) to the dominant mouse induced sedation, decreased social interaction, and caused the dominant mouse to lose this status. |
References | Methods and Procedures | Results and Conclusions |
In rats |
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Karli 1958, 1959a,b | Male rats, selected for muricidal behavior | Chlorpromazine (1–15 mg/kg i.p.) did not affect muricidal behavior despite the sedative effects. |
Janssen et al. 1962 | Male and female rats, selected for muricidal behavior | Chlorpromazine (2.5–40 mg/kg s.c.) haloperidol (1.25–5 mg/kg) and other neuroleptics non-specifically inhibited or abolished muricidal behavior. |
Vergnes and Karli 1963 | Male and female rats which became muricidal after olfactory bulb ablation | Hydroxyzine (30–40 mg/kg, i.p.) abolished muricidal behavior. |
Horovitz et al. 1966 | Female rats, selected for muricidal behavior; rotarod and conditioned avoidance tests for sedation. | Chlorpromazine (ED50=5.5 mg/kg) and fluphenazine (ED50=0.15 mg/kg) non-selectively decreased killing. |
McCarthy 1966 | Rats, separated into groups of spontaneous-killers, capricious killers and non-killers | Chlorpromazine was more effective in blocking pilocarpine-induced muricidal behavior in non-killers than spontaneous killing. |
Loiselle and Capparell 1967 | Male Hooded rats, selected for muricidal behavior; 15 min. observation; also tested motor activity | Chlorpromazine (10–50 mg/kg) slightly decreased muricidal behavior and was sedating. |
Sofia 1969a | Male Long Evans rats, individually-housed, selected for muricidal behavior; rotarod test for neurotoxicity | Chlorpromazine (ED50=9 mg/kg), methotrimeprazine (ED50=120.6 mg/kg), thioridazine (ED50=76.1 mg/kg) and thiothixene (ED50=100 mg/kg) non-selectively reduced killing behavior. |
Goldberg 1970 | Male Long-Evans rats, individually housed for 6 weeks; selected for muricidal behavior; rotarod test for neurotoxicity | Chlorpromazine (5.6 mg/kg i.p.) decreased killing at doses which caused neurotoxicity. |
Valzelli and Bernasconi 1971, 1976 | Male Wistar rats, individually housed for 6 weeks; selected for muricidal behavior | Chlorpromazine (5 mg/kg), propericiazine (1 mg/kg), haloperidol (0.5, 1 mg/kg) and triperidol (1 mg/kg) have antimuricidal activity which may be secondary to sedative effects. |
Ueki et al. 1972 | Male rats, individually housed, received olfactory bulbectomies or electrolytic lesioning of the septum or amygdala; selected for "emotionality" and mouse-killing | Chlorpromazine (5, 10 mg/kg i.p.) decreased muricide, attack response to an inanimate object, and motor activity in olfactory bulbectomized and septal rats. |
Kostowski and Czlonkowski 1973 | Male Wistar rats, individually- or group-housed, separated into "killers" and "non-killers" | Isolated rats were less sensitive to cataleptic effects of chlorpromazine (5 mg/kg s.c.) and haloperidol (0.1, 0.2 mg/kg) than group-housed; "killers'' were less sensitive to chlorpromazine, "non-killers" were less sensitive to haloperidol. |
Barnett et al. 1974 | Male Long-Evans rats, selected for muricidal behavior. | Benzazepine (SCH 12679, ED50=5.6 mg/kg i.p.) and perphenazine (ED50=0.9 mg/kg i.p.) selectively reduced killing. |
Valzelli and Bernasconi 1976 | Male Wistar rats, individually-housed, screened for muricidal behavior; subjected to a single electric shock during test | Chlorpromazine (5 mg/kg i.p.) and haloperidol (1 mg/kg) non-selectively decreased muricidal behavior; propericiazine (1 mg/kg) and triperidol (1, 7.5 mg/kg) were ineffective. |
In ferrets |
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Schmidt and Apfelbach 1977 Schmidt 1979, 1983 | Ferrets were tested for predatory behavior toward Wistar rats. | Haloperidol (0.14, 0.6 mg/kg, i.m.), metoclopramide (10 mg/kg i.m.) and tiapride (16 mg/kg i.m.) increased the efficiency of the predatory behavior. Clozapine (10 mg/kg), sulpiride (40 mg/kg i.p., 90 mg/kg i.m.) and chlorpromazine (4 mg/kg) non-specifically decreased predatory behavior by causing sedation. |
In cats |
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Leaf et al. 1978 | Male and female cats, selected for muricidal behavior | Chlorpromazine (1-8 mg/kg) and haloperidol (0.0625-0.5 mg/kg) did not inhibit muricidal behavior. |
Literature Reviews |
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Delini-Stula and Vassout 1979 | Review of the effects of drugs on aggressive behavior (51 references spanning 1956 to 1978) | Antipsychotic drugs have aggression-decreasing effects which may be secondary to their inhibitory effects on overall behavior; antipsychotics do not effectively decrease predatory aggression. |
Valzelli 1979 | Review of the effects of sedative and anxiolytic drugs on aggression (129 references spanning 1948 to 1979) | Thioridazine appears to be the most selectively antiaggressive phenothiazine; among the butyrophenones, azaperone appears to be selective for aggressive behavior; other phenothiazines and butyrophenones have non-selective effects on aggressive behavior. |
Miczek and Winslow 1987 | Review of research on the psychopharmacology of aggression (over 350 references spanning 1928 to 1986) | The aggression-inhibiting effects of antipsychotic drugs in most pre-clinical experimental paradigms are secondary to their sedative effects. |
Miczek et al. 1994 | Review of current pharmacotherapeutic approaches to the management of violence and aggression (97 references spanning 1959 to 1991) | The suppressive effects of typical neuroleptic drugs, SCH 23390 and raclopride are part of an overall suppression of active behavior. |
TABLE 7B: Effects of Antipsychotics on Aggression in Humans
References | Methods and Procedures | Results and Conclusions |
Behavior Disorders in Juveniles |
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Shaw et al. 1963 | 91 male and female emotionally disturbed children (symptoms included aggressiveness), aged 7–15; behavior evaluated by nursing staff; placebo controlled, double-crossover design | 68% of subjects showed some improvement of symptoms with phenothiazine (trifluoperazine, thioridazine, triflupromazine, fluphenazine) treatment, thioridazine produced the highest percentage of improvement; side effects were drowsiness, apathy and some extrapyramidal dysfunctioning. |
Alderton and Hoddinott 1964 | 9 male children, ages 6–12, some diagnosed with mild brain damage or behavior disorder, all diagnosed as aggressive and hyperactive; aggressive and other symptoms rated as present or absent; placebo-controlled, double-blind | Thioridazine (25 mg t.i.d.) significantly decreased aggressive and destructive symptoms as well as hyperactivity. |
Vialatte 1966 | 51 children with behavioral disorders (including aggression in 29 cases), ages 3 months–14 years; behavior evaluated by parents; no control group | Thioridazine (1–2 mg/kg/day) decreased aggressiveness in all 29 cases. |
Alexandris and Lundell 1968 | 21 male and female institutionalized children, ages 7–12, diagnosed as hyperactive; 5-point rating scale for hyperactive, aggressive, and other behaviors; placebo-controlled, double-blind | Thioridazine (15–150 mg/day for 6 mos.) significantly decreased hyperactivity and aggression scores. |
Cunningham et al. 1968 | 12 children, ages 8–13, who had shown aggressive, hyperactive or destructive behavior; 3-point rating scale for behavior, rated by nursing staff and teacher; reaction time, pegboard, "twisting path", Woodworth-Wells substitution and learning test administered; placebo-controlled double-blind cross-over design | Haloperidol (0.25–1.5 mg b.i.d.), administered for four weeks with benzhexol (1 mg b.i.d., to minimize side effects) caused significant decreases in hyperactivity, destructiveness, resentfulness and aggressiveness; benzhexol alone also decreased hyperactivity; side effects of haloperidol included apathy, sleepiness and transient muscle pain, as well as slower test times. |
Ucer and Kreger 1969 | 50 male and female retarded, emotionally disturbed children, ages 7–12; affective and behavioral symptoms including hyperactivity and aggression were rated; double-blind, no placebo group | Haloperidol (0.75–3.75 mg/day) decreased aggressiveness in 52% and increased aggressiveness in 16% of subjects; thioridazine (15–75 mg/day) decreased aggressiveness in 14.2% (not significant) and increased aggressiveness in 4.8%; minor side effects. |
Faretra et al. 1970 | 60 male and female disturbed children, 87% of them childhood schizophrenics, ages 5–12; rated by investigator, double blind, no placebo group | Overall, haloperidol (0.25–1.25 mg t.i.d.) improved 57% and fluphenazine (0.75–3.75 mg/day) improved 67% of patients; haloperidol decreased assaultiveness scores after 4 weeks but fluphenazine did not. |
Ojeda 1970 | 35 male and female children with symptoms including hyperactivity and aggressiveness, 21 with childhood schizophrenia and 8 with minimal brain damage syndrome, ages 6–12; 5-point rating scale; placebo controlled, double-blind | Thioridazine (100–400 mg/day for 21 weeks) improved symptoms in all 20 patients, placebo improved symptoms in 8 of 15 patients; no side effects reported. |
Sprague et al. 1970 | 12 male emotionally disturbed children, mean age 7.8 years; tested performance on a recognition task, activity level; observed deviant behavior in the classroom, attention to school work and contact with teachers; placebo controlled | Thioridazine (0.75, 1.0 mg/kg/day) decreased accuracy and increased reaction time in the recognition task without affecting activity levels; thioridazine did not significantly affect deviant classroom behavior, contact with teachers or attention; methylphenidate increased accuracy, attention and cooperative behavior while decreasing reaction time and hyperactivity. |
Le Vann 1971 | 61 male and female mentally retarded children exhibiting symptoms of hostility, aggressiveness and compulsiveness, ages 5–12; rated by investigator, double-blind, no placebo | Haloperidol (1–2 mg/day) improved 95% and chlorpromazine (41–140 mg/day) improved 30% of patients; haloperidol was more effective at reducing hostile, impulsive and aggressive symptoms; some side effects (drowsiness), symptoms of one patient on haloperidol worsened. |
References | Methods and Procedures | Results and Conclusions |
Bartunkova et al. 1972 | 21 male and female children with symptoms of motor restlessness, insubordination and aggressiveness, ages 10–15; 7-point rating scale; double-blind | Chlorpromazine and propericiazine reduced aggressivity, insubordination and motor restlessness. |
Campbell et al. 1972 | 10 severely disturbed male and female children (6 schizophrenic, 1 autistic), ages 3–6, matched for motor activity and prognosis; half were administered chlorpromazine and half were administered lithium carbonate, double-blind cross-over design | Chlorpromazine (15–45 mg/day for 8–10 weeks) slightly but non-significantly decreased psychotic speech, withdrawal and stereotypy; slightly but non-significantly increased responsiveness, vocabulary, attention span and speech initiation; EEG effects inconclusive; side effects included sedation and worsening of schizophrenic symptoms; not specific to aggression. |
Minde et al. 1972 | Follow-up study of 91 hyperactive and aggressive children, ages 11–17, initially seen 5 years previously; were treated with chlorpromazine or d-amphetamine | Symptoms diminished with maturity but subjects' behavior still more problematic than controls; psychological adjustment did not appear to be dependent on duration of drug therapy; drug therapy alone not sufficient to improve behavior. |
Aman and Werry 1975 Werry and Aman 1975 | Male and female hyperactive and aggressive children, ages 4–12; placebo-controlled, double-blind | Haloperidol (.035 mg/kg, acute) had no effect on cardiovascular function beyond a slight and transient increase of heart rate; low doses (.025 mg/kg) increased cognitive functioning and high doses (.05 mg/kg) decreased functioning; improvement seen mostly in low-complexity tasks; methylphenidate appears more effective overall. |
Saletu et al. 1975 | 62 male and female hyperactive children with symptoms which included aggressiveness, ages 6–13; Global Clinical Impression Rating Scale, Parents' Questionnaire, Teachers' Questionnaire, measurement of visual evoked potentials; double blind, placebo-controlled | Thioridazine (20–80 mg/day) improved symptomatology but was less effective than d-amphetamine; short latencies and small amplitudes of visual evoked potentials preceding treatment were predictors of good therapeutic response to thioridazine. |
Gittelman-Klein et al. 1976 | 155 male and female children, ages 6–12, diagnosed as hyperactive; 4-point rating scale completed by parents, 6-point clinical evaluation scale; 8-point Global Improvement Scale by teachers, parents, clinicians; placebo-controlled, single-blind | Thioridazine (50–300 mg/day, alone or with 52 mg/day methylphenidate for 12 weeks) did not improve symptoms after 4 or 12 weeks treatment; children receiving thioridazine with methylphenidate were improved; mild side effects (decreased appetite, sleep difficulties) were noted. |
Campbell 1987 | Autistic and conduct disorder aggressive children | Haloperidol facilitated learning in retarded autistic children and did not induce side effects, but did slow reaction time and performance on Porteus Mazes in non-retarded aggressive children as well as induce Parkinsonian side effects. |
Criminal Violence |
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Jirgl et al. 1970 | 15 aggressive and auto-aggressive delinquents with psyphopathic personal features; tested using Clyde's mood scale, Knobloch-Hausner neuroticism questionnaire N-5, Zunge depression scale, multiple affect adjective check list and others; no control group | Propericiazine (doses not mentioned) decreased hostility, depression and aggressivity markedly; emotional liability and thinking were moderately improved; side effects were somnolence and muscular rigidity. |
Scarnati 1986 | 47 male prisoners, ages-55, 44 had committed violent crimes; 25 diagnosed with paranoid schizophrenia, 6 diagnosed with bipolar disorder, 29 were alcohol and/or drug abusers; observations by prison psychiatrist | Most inmates (n=15) were being treated with fluphenazine deconate (24–62.5 mg/2 weeks) or thioridazine HCl (5 inmates, 100–500 mg/day); schizophrenic patients treated with antipsychotics show better cognitive functioning than untreated schizophrenics; this prison population appears to require higher than normal doses of antipsychotic medication. |
References | Methods and Procedures | Results and Conclusions |
Inpatient Studies |
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Schizophrenic patients |
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Overall et al. 1964 | 68 male schizophrenic and 77 male depressed inpatients, ages 25–76; evaluated before and 4 weeks after treatment commenced; Brief Psychiatric Rating Scale (BPRS), Manifest Depression Scale of the Inpatient Multidimensional Psychiatric Scale (IMPS), Manifest Depression Scale of the Minnesota Multiphasic Personality Inventory (MMPI) | Thioridazine (mean daily dose 507–605 mg) reduced hostility, suspiciousness and overall pathology more effectively than imipramine in both patient groups. |
Kellam et al. 1967 | Over 340 acute schizophrenic inpatients; assessed before and 6 weeks after drug treatment; global ratings by psychiatrist, psychologist and nurse, Inpatient Multidimensional Psychiatric Rating Scale completed by psychiatrist or psychologist, Ward Behavior Rating Scale completed by nurse; placebo controlled, double blind | Chlorpromazine, fluphenazine, and thioridazine decreased hostility and aggression scores; regardless of drug or placebo treatment, patients in low disturbed behavior wards improved more than patients in high disturbed behavior wards. |
Ebert et al. 1977 | 36 male and female schizophrenic inpatients, ages 19–41; global ratings, Gottschalk's Five Minute Verbalization Task, Rorschach tests given before and 5 and 13 weeks after initial drug administration; behavior ratings by clinicians and nurses; double-blind | Chlorpromazine, fluphenazine and acetophenazine decreased overall and aggressive primary process expression at 13 weeks; this was correlated with degree of illness but not with scores on the Rorschach at 5 weeks. |
Yesavage 1982 | 58 male violent schizophrenic inpatients, ages 22–58; antipsychotic serum levels and instances of assaulted-related behavior on the ward measured for 1 week | Mean serum level after thiothixene treatment was 13.3 ng/ml; significant correlations were found between lower serum levels and higher incidence of assaultive behavior. |
Appelbaum et al. 1983 | Retrospective study of 93 inpatients known to have committed violent acts within 6 months of the study, diagnosed with schizophrenia, senile dementia or manic-depressive psychosis; compared medication received before and after patients committed acts of violence with drug treatment of non-violent control group | No significant differences were found in drug or doses prescribed for violent and nonviolent groups; majority of violent acts committed by patients taking low (less than 400 mg/day) doses of antipsychotic medication (chlorpromazine, haloperidol, fluphenazine deconate). |
Herrera et al. 1988 | 16 male schizophrenic inpatients proven resistant to previous neuroleptic treatment, ages 25–44; global effects, motor effects and violence (Lion's Scale of Inpatient Violence) rated by research and nursing staff; placebo-controlled, double-blind | Chlorpromazine (1800 mg/day for 6 weeks, with 6 mg benztropine), clozapine (900 mg/day), or placebo treatment resulted in significantly fewer violent episodes than haloperidol (max dose 60 mg/day for 6 weeks, with 6 mg benztropine); in a subgroup of patients, a moderately high-dose of haloperidol can increase violent behavior (correlated with akathesia). |
Mentally Retarded |
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Llorente 1969 | Retrospective study of 65 male and female mentally retarded and aggressive inpatients, ages 7–63; behavior rated on a 7-point scale | Thioridazine (100–800 mg/day) significantly decreased aggressiveness, assaultiveness and hyperactivity. |
Elie et al. 1980 | 253 male and female aggressive, mentally retarded inpatients; 5-point rating scale of aggressive and other symptoms and CGI assessed by chief investigator and nursing staff; placebo-controlled, double-blind | SCH 12679 (benzazepine, 100 mg 4 times daily) decreased aggressive symptoms within 2 weeks, reduced agitation and hyperactivity; thioridazine (50 mg 4 times daily) increased aggressive behavior; SCH 12679 caused side effects including sedation, anorexia, GI disturbances. |
Hacke 1980 | 18 female mentally retarded aggressive and self-injurious inpatients, ages 14–32 | Melperone (a butyrophenone, 100–300 mg/day) significantly reduced aggressive and auto-aggressive behavior; no severe side-effects were found. |
De Cuyper et al. 1985 | 21 female mentally retarded inpatients displaying chronic aggressive behavior, ages 26–76; 2 scales for aggressive behavior; double-blind placebo-controlled | Milenperone (a benzimidazolone propylamine, 10 mg b.i.d. for 6 weeks), added as an adjuvant to previously administered psychotropic medication, did not significantly reduce aggressiveness; side effects included orofacial dyskinesias. |
Read and Batchelor 1986 | 21 male and female mentally handicapped inpatients who exhibited severe violent and/or self-injurious behavior, ages 21–54; global observations; no placebo control | Haloperidol decanoate (200–300 mg every 28 days with procyclidine, 5 mg bd or tds) controlled aggression and self-injury in those patients treated and also decreased the general level of aggression in untreated patients. |
References | Methods and Procedures | Results and Conclusions |
Other |
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Ananth et al. 1972 | 56 male and female psychotic inpatients, ages 18–60; drug was administered in emergency situations; 3-point aggression scale; double-blind, chlorpromazine administered as control | Both propericiazine (20 mg i.m.) and chlorpromazine (100 mg) significantly improved behavior without significant side effects; propericiazine was superior in reducing agitation and aggression, chlorpromazine was superior in reducing excitement. |
Tardiff 1982, 1983, 1984 | Survey of the use of drugs in treating over 5,000 male and female assaultive and nonassaultive inpatients; most medicated with neuroleptics (haloperidol, chlorpromazine, thioridazine, thiothixene) alone or in combination with anticonvulsants (phenytoin); rated using NOSIE scale of psychopathology and behavior | The use of neuroleptics, except chlorpromazine, was correlated with an increased need for emergency medication, restraint or seclusion; there is no evidence that this relationship is causal. |
Brenner et al. 1984 | 20 male and female inpatients with significant aggressive or auto-aggressive behavior, ages 62–90; measured aggressive, auto-aggressive, spontaneous and initiative behavior as well as cognitive performance; double-blind cross-over design, pipamperone used as reference | Febarbamat (3–8 150-mg tablets/day for 8 weeks) and pipamperone (3–8 20 mg tablets/day) did not significantly differ in effects on social behavior; results of cognitive tests were inconclusive. |
Gelders et al. 1984 | 34 male and female out- and inpatients, aged 24–56; 16 of these were epileptics and 19 were alcoholics; behavior evaluated with a 22-item rating scale; no placebo control | Milenperone (2 mg b.i.d., alone or as an adjuvant to existing medication) significantly reduced verbal and physical aggression in both in- and outpatients; side effects were observed in 2 patients. |
Schulte 1985 | 5 cases of violent behavior associated with haloperidol treatment (in- and outpatients) | Violent reactions to haloperidol which are associated with akathesia may occur up to 24 hrs after treatment; a follow-up should be done within 24–48 hrs of treatment. |
Fugham et al. 1989 | 48 male and female elderly demented, aggressive inpatients; symptoms rated on a 4-point scale, 1,2, and 4 weeks after treatment; Comprehensive Psychopathological Rating Scale and GBS scale for dementia | Both zuclopenthixol (max mean daily dose 5.1 mg) and haloperidol/levomepromazine (max mean daily dose 1.6/7.6 mg) reduced aggressiveness within 1 week of treatment; zuclopenthixol was more effective. |
Outpatient Studies |
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Schizophrenic Patients |
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Cohen et al. 1968 | 126 male and female schizophrenic outpatients who scored highly on a measure of social aggression at home (Explicit opposition), ages 18–42; interviews of patient by psychiatrist and interviews of close relatives used to measure social aggression; double-blind placebo-controlled | Chlorpromazine (mean daily dose 100–400 mg) decreased aggressive symptoms in patients living in homes judged "low conflict and tension" but chlorpromazine and promazine were equally ineffective for patients living in homes judged "high conflict and tension". |
Rada and Donlon 1972 | 27 male and female schizophrenic outpatients, ages 21–58; placebo-controlled, double-blind | Piperacetazine (up to 160 mg/day) and thioridazine (up to 800 mg/day) both improved anergia and thinking disorder; hostility, suspiciousness and unusual thought content were significantly reduced with thioridazine. |
Mentally Retarded Patients |
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Deberdt 1976 | 188 male and female outpatients showing behavior disturbances, 50 of these mentally retarded, ages 3–100; 4-point rating scale of symptoms; no placebo control | Pipamperone (median optimum daily dose 95 mg for mentally retarded subjects, in nonmentally retarded subjects 47 mg for children and 80 mg for adults and aged subjects, 4 weeks) significantly reduced aggressive, destructive, and other behavior; few side effects reported (sleepiness). |
Other |
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Keckich 1978 | Case study of a 29 year-old outpatient man diagnosed with sociopathic personality and transvestism who had a history of drug abuse and hostility | Haloperidol treatment (2–4 mg/day) along with imipramine treatment (100 mg/day) was prescribed to control depression, violent tendencies; akathitic side effects from haloperidol provoked an urge to assault. |
Clinton et al. 1987 | 136 male and female patients treated in an emergency department for violent behavior due to alcohol intoxication, head trauma and personality disorder, among others; response categorized as +,-, no effect | Haloperidol (mean cumulative dose=8.2 mg i.m., i.v. or p.o.) alleviated violent behavior in 113 patients, had no effect in 3 patients; complications were observed in 4 patients. |
References | Methods and Procedures | Results and Conclusions |
Literature Reviews |
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Lion 1975 | Review of the use of drug therapy for aggression (47 articles spanning 1957–1975) | It is impossible to state whether either the phenothiazines, thiothixenes or butyrophenones are better for the treatment of aggression; this depends on the patient. |
Winsberg et al. 1976 | Discussion of drug therapy in hyperactive and aggressive children | Psychostimulant and tricyclic treatment is preferable to antipsychotic treatment because these drugs are less toxic; chlorpromazine and thioridazine can have effects within one day in children who are responders; haloperidol can be useful in children who do not respond to stimulants, tricyclics, or phenothiazines. |
Eichelman 1977 | Review of the use of pharmacological therapy in treating aggression (23 articles spanning 1968–1977) | Pharmacological intervention should be used to treat the underlying cause of the aggressive behavior. Antipsychotics should be used for patients whose violence is secondary to their psychoses, delusions or hallucinations. |
Itil and Mukhopadhyay 1978 | Review of the use of drug treatment in the management of aggressive behavior associated with various mental disorders and drug abuse (87 articles spanning 1937–1977) | Antipsychotics can be used successfully to treat aggression associated with schizophrenia, epilepsy, mental retardation, personality disorders, drug abuse, and children with minimal brain dysfunction; side effects include sedation; no drug treats aggression specifically. |
Aman and Singh 1980 | Review of the effectiveness of thioridazine in treating disturbed children (24 articles spanning 1958–1978) | Only 34 of 101 dimensional ratings of behavior are successfully influenced by thioridazine treatment, among those are aggressiveness, hyperactivity, and mood; drowsiness is a prominent side effect; effects on cognitive functioning are inconclusive. |
Itil 1981 | Review of the pharmacological management of human aggressive behavior (71 references spanning 1959–1980) | Chlorpromazine, triflupromazine, thioridazine, pericyazine, fluphenazine, thiothixene, and haloperidol are recommended for aggression related to psychosis, dementia, minimum brain dysfunction, mental retardation, antisocial personality and conduct disorder; antipsychotics are not recommended for aggression due to epilepsy. |
Leventhal and Brodie 1981 | Review of the psychopharmacology of aggression and violence (69 references spanning 1968–1979) | Antipsychotics are potent antiaggressive agents in psychotic and nonpsychotic patients but the benefits of these substances must be weighed against their potential for provoking debilitating side effects. |
Werry 1981 | Review of the effects of drugs on learning in children (44 articles spanning 1937–1980) | Data on the effects of antipsychotics and learning are scarce and inconclusive. |
Sheard 1983 | Review of the psychopharmacology of aggressive behavior in animals and humans (60 articles spanning 1966–1981) | Careful use of neuroleptics is recommended for the management of aggression associated with violent psychotic states, alcohol withdrawal, amphetamine psychosis, mental retardation and children with minimal brain damage. Neuroleptics are less useful for treating aggression associated with epileptic seizures, personality disorders, phencyclidine psychosis and affective disorders. |
Conn and Lion 1984 | Review of drug therapy in treating violent patients (11 articles spanning 1972–1980) | No single drug is available to treat aggression, the pharmacotherapy used depends on the patient's symptoms; antipsychotics are useful for controlling aggressive behavior in emergency situations and in patients with thought disorders; small doses may be useful for paranoid patients but also may worsen the aggression by causing the patient to feel out of control. |
Tupin 1985 | Review of drug therapy in managing violent patients (35 articles spanning 1970–1983) | High potency antipsychotics, along with barbiturates and occasionally benzodiazepines, are useful for controlling violence in short-term emergency situations; for long-term management, clinical assessment should be done to determine appropriate treatment. |
Cherek and Steinberg 1987 | Review of the effects of drugs on human aggression (191 references spanning 1937–1986) | Further research is needed to delineate factors predicting favorable response to neuroleptics in non-psychotic patients. |
Yudofsky et al. 1987 | Review of the pharmacological treatment of aggressive behavior in humans | No medication specifically treats aggression, however antipsychotics are used most commonly; the effectiveness of antipsychotics is usually due to their sedative effects; because of their debilitating side effects, antipsychotics should not be used chronically to treat aggression. |
Brizer 1988 | Review of pharmacotherapy in managing aggressive patients (145 articles spanning 1962–1987) | Antipsychotics are reported to be useful in treating aggressive schizophrenics, behaviorally disordered children, and patients with borderline personality disorder, organic brain syndromes, alcohol- and drug-induced aggression, or psychoses; however many studies are methodologically flawed. |
Itil and Reisberg 1978 | Discussion of drug treatment in aggressive patients (30 articles spanning 1944–1978) | Chlorpromazine (25–100 mg i.m.) is favored for acute emergency use but blood pressure must be monitored; in persistent acute aggression (beyond 48 hours) ECT treatment or a combination of chlordiazepoxide and antipsychotic medication is useful. |
Klar and Siever 1984 | Discussion of drug therapy in treating aggression (43 articles spanning 1967–1983) | Impulsive aggressive behavior in psychotic patients is effectively treated with antipsychotic drugs. |
TABLE 8A: Effects of Antidepressant and Monoamine Oxidase Inhibitor Drugs on Aggression in Animals
References | Methods and Procedures | Results and Conclusions |
A. NORADRENERGIC REUPTAKE BLOCKERS |
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Isolation-induced Aggression |
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Cook and Weidley 1960 | Male mice; one subject drug treated; group-housed opponent | Imipramine (ED50:12.7 mg/kg i.p.) decreased attack behavior. |
Da Vanzo et al. 1966 Kršiak 1975b Kršiak 1979 Kršiak et al. 1981 | Male albino C57B1/10J and ICR mice; isolated subject drug treated; group-housed opponent | Neurotoxic doses imipramine (ED50:31.2 mg/kg i.p.) and amitriptyline (ED50:11.2 mg/kg i.p.) inhibited fighting behavior. 25 mg/kg i.p. desipramine in conjunction with 0.5 mg/kg i.c.v. 6-OHDA increased attack behavior. |
Valzelli et al. 1967 Valzelli and Bernasconi 1971 | Groups of 3 male Swiss albino mice; all subjects drug treated; 5 point aggression scale | 10–30 mg/kg i.p. amitriptyline inhibited aggression in 100% of the subjects. 20 mg/kg i.p. imipramine inhibited aggression in 25% of the subjects. 20 mg/kg i.p. desipramine did not inhibit aggression. |
Le Douarec and Broussy 1969 Sofia 1969b Wenzl et al. 1978 Tobe et al. 1981 | Male and female CD, Swiss and NMRI mice; both subjects drug treated | 5–20 mg/kg i.p. imipramine dose dependently decreased attacks, exploratory and motor behavior. Thiazesim (ED50:22.3 mg/kg i.p.) decreased fighting. Amitriptyline (ED50:15.6 mg/kg p.o.), 31.6 mg/kg p.o. nortriptyline and MCI-2016 (ED50:44.0 mg/kg p.o.) inhibited aggression. 75 mg/kg p.o. amitriptylinoxide inhibited biting due to sedation. |
van Riezen et al. 1973 | Male Swiss mice; both subjects drug treated | Imipramine (ED50:7 mg/kg s.c.) and O177 (5-methylaminocetyl-6-methyl-5, 6-dihydrophenanthridine-HCI; ED50:11 mg/kg s.c.) decreased fighting without motor impairment. |
Delini-Stula and Vassout 1981 | Male albino NMRI mice; acute and 21 day treatment; both subjects drug treated | Acute administration of 10, 25 mg/kg i.p. imipramine did not affect aggression. Chronic treatment with 10 mg/kg imipramine decreased the proportion of animals fighting by 30%. Acute administration of 10, 15 mg/kg i.p. maprotiline or 3, 7.5 mg/kg i.p. amitriptyline decreased fighting by 30–50% which showed no signs of tolerance after chronic treatment. |
Sieber et al. 1982 | Male C3H/HeJ mice; resident or intruder drug treated | 10 mg/kg p.o. imipramine to resident or intruder decreased social investigation and increased aggressive behavior. |
Yoshimura and Ogawa 1984 | Male mice; resident or intruder drug treated | When administered to the resident, 5–20 mg/kg i.p. imipramine suppressed bites and aggressive postures. |
Oehler et al. 1985b | Male albino AB/Jena mice; 3 point scale | 20 day administration of 5 mg/kg (in water supply) desipramine had no effect on aggressivity. |
Pain-induced aggression and defense |
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Allikmets and Lapin 1967 | Footshock to pairs of albino rats with and without amygdaloid lesions; both subjects drug treated | Acute administration of 20 mg/kg i.p. imipramine increased aggressiveness in lesioned animals. 10 day administration of 5–20 mg/kg lowered the threshold for aggressiveness in lesioned animals. Acute and chronic administration of 5 mg/kg i.p. desipramine slightly enhanced aggressiveness in lesioned animals. |
Lapin 1967 | Footshock to pairs of male and female albino, BALB, C57Br and C57B1 mice; both subjects drug treated | 0.05 mM/kg i.p. desipramine and imipramine modestly increased aggressiveness. |
References | Methods and Procedures | Results and Conclusions |
Sofia 1969b Irwin et al. 1971 van Riezen et al. 1973 Rolinski and Herbut 1981 Tobe et al. 1981 | Footshock to pairs of male and female albino mice; both subjects drug treated | Neurotoxic doses of imipramine (ED50:22 mg/kg i.p.), desipramine (ED50:45.6 mg/kg i.p.) and amitriptyline (50, 100 mg/kg p.o.) decreased fighting and increased escape responses. 100–200 mg/kg p.o. MCI-2016 dose dependently decreased fighting. Up to 32 mg/kg s.c. O177 (5-methylaminoacetyl-6-methyl-5, 6-dihydrophenanthridine) and 50 mg/kg i.p. thiazesim had no effect on fighting. |
Tedeschi et al. 1969 | Footshock to pairs of male mice; both subjects drug treated | Amitriptyline (ED50:39.8 mg/kg p.o.) decreased fighting and produced motor impairment. 20 mg/kg i.p. imipramine produced no effect on fighting. |
Crowley 1972 Crowley and Rutledge 1974 Anand et al. 1977 | Footshock to pairs of male Sprague-Dawley rats; both subjects drug treated | 10, 20 mg/kg i.p. imipramine dose dependently decreased fighting duration and was without effect on motor behavior. |
Burov 1975 | Footshock to pairs of male albino rats; both subjects drug treated | 5 mg/kg i.p. amitriptyline, imipramine increased the number of fight cycles. |
Eichelman and Barchas 1975 Prasad and Sheard 1982 Prasad and Sheard 1983a,b | Footshock to pairs of male Sprague-Dawley rats; both subjects drug treated | Acute administration of 10 mg/kg i.p. desipramine did not change fighting. 2–5 day administration of 10 mg/kg i.p. b.i.d. amitriptyline, desmethylimipramine, imipramine or 10, 15 mg/kg i.p. desipramine potentiated attacks. |
Sheard et al. 1977 | Footshock to pairs of male albino Sprague-Dawley rats with and without 30 ug/kg i.p. LSD; both subjects drug treated | 5 mg/kg i.p. desipramine pretreatment antagonized LSD-enhanced fighting while having no effect on fighting without LSD. |
Bell and Brown 1979 | Footshock to pairs of male Sprague-Dawley rats; both subjects drug treated | 1–10 mg/kg i.p. thiazesim produced no effect on aggression. |
Mogilnicka and Przewlocka 1981 Mogilnicka et al. 1983 | Footshock to pairs of male albino Wistar rats; acute and 10 day administration; both subjects drug treated | Acute administration of 10 mg/kg i.p. amitriptyline, imipramine, mianserin, iprindole, maprotiline or (+,-, ±) oxaprotiline produced no effect on fighting. Chronic administration of 10 mg/kg i.p. b.i.d. amitriptyline, imipramine, mianserin, iprindole, maprotiline or (+,-, ±) oxaprotiline increased the frequency and duration of fighting. |
Valdman and Poshivalov 1986 | Footshock to pairs of male CC57W mice; 7 day pretreatment with 0.5 mg/kg i.p. b.i.d. reserpine; both subjects drug treated | 7 day administration of 10 mg/kg i.p. trazodone reduced timid-defensive and restored aggressive behavior due to nociceptive stimulation. |
Aggression due to omission of reward |
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Kamioka et al. 1977 | Lever pressing in male macaque monkeys; reinforcer alternated between food delivery and tail shock to conspecific; one subject drug treated | 10 mg/kg p.o. imipramine administration to either subject did not alter the number of shock deliveries. |
Kampov-Polevoi 1978 | Escape from water competition in pairs of male albino Wistar rats; one animal drug treated | 1, 5 mg/kg i.p. amitriptyline 0.3, 2.5 mg/kg i.p. imipramine dose dependently decreased effective attacks by the dominant rat. 1, 5 mg/kg amitriptyline and 0.15–2.5 mg/kg imipramine dose dependently increased defensive and offensive abilities of subordinate rats. |
Defensive aggression induced by brain stimulation |
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Penaloza-Rojas et al. 1961 | Electrical stimulation of the posterior hypothalamus in adult cats | 2–5 mg/kg i.p. imipramine decreased and 8–10 mg/kg increased the response threshold for rage during hypothalamic stimulation. |
Allikmets and Delgado 1968 Allikmets et al. 1968 | EEG recordings and ''spontaneous" behavior after electrical stimulation of the amygdala and hippocampus in restrained monkeys (Macaca mulatta) | 100 uL imipramine and 100 uL amitriptyline increased the threshold necessary for aggressiveness and vocalizations and suppressed EEG activity in the amygdala. |
Baxter 1968b | Hissing response via stimulation of the perifornical-ventromedial hypothalamus in cats | 3–12 mg/kg i.p. imipramine produced no effects on the hissing response and ataxia. |
References | Methods and Procedures | Results and Conclusions |
Dubinsky and Goldberg 1970 Dubinsky et al. 1973 | Hissing response and attack behavior via electrical stimulation of the perifornical region of the hypothalamus in adult male and female cats | Imipramine (ED50:8.5 mg/kg i.p.) decreased attacks with inconsistent effects on the hissing response. 12 mg/kg i.p. desipramine inhibited attack in 3 of 6 cats. |
Malick 1970 | Hissing response via electrical stimulation of the perifornical region of the hypothalamus in cats | 5 mg/kg i.p. imipramine lowered and 10 mg/kg increased the threshold to elicit the hissing response. 10, 20 mg/kg i.p. thiazesim increased "irritability" but failed to consistently decrease hiss threshold. |
Funderburk et al. 1970 | Hissing response via electrical stimulation of the perifornical region of the hypothalamus in adult male and female mongrel cats | 5 mg/kg i.p. amitriptyline, desipramine and imipramine elevated the threshold to elicit the hissing response. |
Lesion-induced aggression |
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Reis and Fuxe 1964 | Sham rage in male and female adult cats produced by decerebration (lesions from the superior colliculus to the optic chiasm) | 5–10 mg/kg i.v. protriptyline increased sham rage for up to 60 minutes; rage was abolished with 5 mg/kg i.v. haloperidol. |
Malick et al. 1969 Sofia 1969b Goldberg 1970 | Biting of an inanimate object in male Long-Evans hooded rats with lesions of the septum, ventral-medial hypothalamus or olfactory bulbs; 3 point aggression scale | Imipramine suppressed aggression in septal (ED50:52.7 mg/kg i.p.) and OB (ED50:42.9 mg/kg) rats, but was inactive in VMH rats. Thiazesim decreased aggression in septal (ED50:24.8 mg/kg i.p.), VMH (ED50:23.5 mg/kg) and OB (ED50:26.1 mg/kg) rats. Desipramine (ED50:45.4 mg/kg i.p.) decreased biting in septal rats. Doses which were effective in suppressing aggression were neurotoxic. |
Ueki et al. 1972 | "Emotionality" (reactions to inanimate bite target handling, tail pinching and mice) in male Wistar King A rats with lesions of the olfactory bulb, septum, or amygdala; 4 point scale | 10, 20 mg/kg i.p. imipramine produced no effects on aggressive reactivity in septal rats except for a dose dependent decrease in muricide. 10, 20 mg/kg i.p. imipramine and 5, 10 mg/kg i.p. amitriptyline dose dependently decreased reactivity in OB rats. Effects were at doses which decreased ambulation and rearing. |
Drug-induced Aggression |
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Lapin 1962 | Groups of ten male albino mice treated with 20 mg/kg s.c. amphetamine; all subjects drug treated | 0.5, 1 mg/kg s.c. imipramine potentiated amphetamine-induced motor excitation and aggressivity. 62.5 mg/kg imipramine decreased vocalizations and biting and motor activity. |
Allikmets et al. 1969 | Male and female cats treated with 200 ug acetylcholine to the amygdala | Pretreatment with 5 mg/kg i.m. imipramine decreased acetylcholine-induced "emotional" reactions, seizures and salivation. |
Fog 1969 | Groups of four male albino Wistar rats pretreated with 200 mg/kg s.c. pargyline; all subjects drug treated | 50 mg/kg s.c. imipramine, desipramine, nortriptyline and amitriptyline induced vocalizations and defensive reactions without stereotypy in 100% of the rats. |
Zetler and Otten 1969 | Vocalizations and reaction to inanimate bite target in male Wistar rats | 2.5–20 mg/kg i.p. imipramine does not induce aggression and vocalizations. 2.5–20 mg/kg imipramine dose dependently increased vocalizations and biting after 30 mg/kg i.p. isocarboxazid or 100 mg/kg i.p. iproniazid, but not 50 mg/kg i.p. phenelzine. |
Schrold 1970 | Pairs of 3–10 day old female White-Leghorn or male New Hampshire chicks; both subjects drug treated | 6.3, 12.5 mg/kg i.p. imipramine, desipramine, 10, 20 mg/kg i.p. protriptyline and 5, 20 mg/kg nortriptyline dose dependently increased the intensity of attack pecks. 5–20 mg/kg i.p. amitriptyline produced no effect on pecking. |
Yen et al. 1970 | Biting of an inanimate object in male ICR mice after administration of 500 mg/kg i.v. dl-DOPA | Imipramine (ED50:11.5 mg/kg i.p.), desipramine (ED50:14 mg/kg i.p.) decreased DOPA-induced biting. Amitriptyline (ED50:34 mg/kg i.p.) decreased DOPA-induced biting at sedative doses. |
Zetler and Hauer 1975 | Vocalizations and biting of an inanimate object in male Wistar rats pretreated with 30 mg/kg i.p. isocarboxazid | 30 mg/kg i.p. imipramine increased vocalizations and attacks to the inanimate object. |
Maj et al. 1979 | Pairs of male Wistar rats treated with 5 mg/kg s.c. apomorphine; both subjects drug treated | 14 day pretreatment with 10 mg/kg s.c. amitriptyline, imipramine, desipramine, mianserin and iprindole produced a 30–60% increased in the proportion of apomorphine-induced fighting pairs. |
References | Methods and Procedures | Results and Conclusions |
Maj et al. 1980 Maj et al. 1981 Maj et al. 1982 Maj et al. 1983 | Groups of four male albino Swiss mice treated with 20 mg/kg clonidine i.p.; all subjects drug treated | Acute: 10 mg/kg i.p. amitriptyline, imipramine, mianserin and iprindole attenuated clonidine induced aggressiveness. 10 mg/kg i.p. (+), (-) oxaprotiline did not affect clonidine-induced aggression. Chronic: Clonidine induced aggression was enhanced at 2, but not 72 hours after 10 day treatment with 10 mg/kg i.p. b.i.d. amitriptyline, imipramine, mianserin, iprindole or (+)oxaprotiline. |
Kostowski et al. 1986 | Groups of 3 male albino Swiss mice administered 10 mg/kg i.p. clonidine; pairs of male Wistar rats administered 10 mg/kg i.p. apomorphine; all subjects drug treated | 21 day pretreatment with 10 mg/kg i.p. desipramine increased the number of biting attacks, vocalizations in mice and increased aggression in rats. |
Aggression by resident toward intruder |
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Avis and Peeke 1979 | Male convict cichlids (Cichlasoma nigrofasciatum); resident drug treated | 0.50, 1.0 mg/L (in aquarium water) imipramine decreased the frequency of attack displays. |
Willner et al. 1981 | Male Lister hooded rats; resident drug treated | 7 day treatment with 5–20 mg/kg i.p. desmethylimipramine dose-dependently increased reactivity to handling. In the home cage, 20 mg/kg increased attacks to intruders, 7.5, 10 mg/kg produced aggressive behavior if period of drug treatment increased or 3–4 day withdrawal period was included. |
Killing |
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Horovitz et al. 1965 Horovitz et al. 1966 Kulkarni 1968 Barnett et al. 1969 Sofia 1969a Goldberg 1970 Salama and Goldberg 1970 Valzelli and Bernasconi 1971 Hitchens et al. 1972 van Riezen et al. 1973 Rush and Mendels 1975 Valzelli and Bernasconi 1976 Eisenstein et al. 1982 Strickland and DaVanzo 1986 | Muricidal behavior in male and female Wistar, Long-Evans, Sprague-Dawley and Holtzman rats | Amitriptyline (ED50:5.1 mg/kg i.p.), imipramine (ED50:8 mg/kg i.p.), desipramine (ED50:9.8 mg/kg i.p.), mianserin (ED50:10.5 mg/kg i.p.), trazodone (ED50:7.2 mg/kg i.p.), bupropion (ED50:15.3 mg/kg i.p.), aletamine (ED50:1.0 mg/kg i.p.), thiazesim (ED50:14.8 mg/kg i.p.), doxepine (ED50:10 mg/kg i.p.), desmethyldoxepine ED50:10 mg/kg i.p.), 10–30 mg/kg s.c. and p.o. OI77 (5-methylaminoacetyl-6-methyl-5,6-dihydro-phenanthridine-HCl) dose dependently decreased muricide with minimal effects on motor coordination. |
Didiergeorges et al. 1968 Malick 1976 Yamamoto and Ueki 1978 Watanabe et al. 1979 Tobe et al. 1981 Hara et al. 1983 Shibata et al. 1983 Hara et al. 1984 Shibata et al. 1984 Iwasaki et al. 1986 | Muricidal behavior in male Wistar and Long-Evans rats with olfactory bulbectomies | Peripheral administration: Imipramine (ED50:25.8 mg/kg i.p.), amitriptyline (ED50:34.0 mg/kg i.p.), desipramine (ED50:3.3 mg/kg i.p.), MCI-2016 (ED50:19.2 mg/kg i.p.), 10–20 mg/kg i.p. doxepine, 5–10 mg/kg i.p. maprotiline and 10–50 mg/kg i.p. lofepramine dose dependently decreased muricide in OB rats. There were no signs of tolerance after 21 day administration. Central administration: Bilateral injections of 5–20 ug imipramine, 10–30 ug amitriptyline or 10 ug doxepine into the medial amygdala, posterior lateral hypothalamus or amygdala suppressed muricide in OB rats. |
Leaf et al. 1969 | Muricidal behavior in male hooded Wesleyan and female albino Holtzman rats | Bilateral administration of 50 ug imipramine or thiazesim to the amygdala produced immediate inhibition of muricide for up to 2 hr. Thiazesim decreased muricide when administered to the medial n. of the amygdala in males and central or basolateral, -medial n. of the amygdala in females. |
Rolinski 1975 | Muricidal behavior in male and female Wistar rats pretreated with 400 mg/kg i.p. PCPA | 20 mg/kg i.p. imipramine suppressed muricide. |
References | Methods and Procedures | Results and Conclusions |
Barr et al. 1976 | Frog killing and muricide in male and female rats | 12 mg/kg imipramine had no effect on attack and kill latencies of mice but inhibited frog kill latencies. |
Leaf et al. 1978 | Muricidal behavior in adult male and female cats | 2–64 mg/kg i.p. imipramine and 4–32 mg/kg i.p. amitriptyline did not inhibit muricide. |
Yamamoto and Ueki 1978 | Muricidal behavior in male Wistar King A rats with midbrain raphe lesions | Imipramine (ED50:17.8 mg/kg i.p.) and desipramine (ED50:25.1 mg/kg i.p.) dose dependently decreased muricide in raphe lesioned rats. |
Schmidt 1979 Schmidt 1980 Schmidt and Meierl 1980 | Rat killing behavior in male ferrets | 10, 40 mg/kg p.o. maprotiline and 17 day administration of 5, 10 mg/kg p.o. b.i.d. imipramine produced no effects on capture elicitation and attack. |
Fujiwara et al. 1980 | Muricidal behavior induced by chronic 6 mg/kg i.p. D9-THC administration in Male Wistar King A rats | 5–20 mg/kg i.p. imipramine, 10–30 mg/kg i.p. amitriptyline, 10–20 mg/kg i.p. doxepine, 5–10 mg/kg i.p. maprotiline, 10–50 mg/kg i.p. lofepramine and 5–20 mg/kg i.p. desipramine dose dependently decreased muricide. |
Kostowski et al. 1984 | Muricidal behavior in male Wistar rats with or without 3 150 mg/kg p.o. PCPA pretreatments | 2.5, 5 mg/kg i.p. desipramine and nomifensine dose dependently decreased spontaneous and PCPA-induced muricide. Anti-muricide effects were greater in PCPA treated animals. |
Al-Khatib et al. 1987 | Muricidal behavior in adult male Wistar King-A rats with lesions of the nucleus accumbens | 30 mg/kg i.p. imipramine, 15 mg/kg i.p. nomifensine and 15 mg/kg i.p. mianserin suppressed muricide. |
Literature Reviews |
|
|
Valzelli 1967 | Review of over 200 articles between 1934 and 1966 on drugs and aggressiveness | Antidepressants (amitriptyline, desipramine, imipramine and thiazesim) decrease aggression in isolation-, lesion-induced and muricide paradigms. |
Karli et al. 1968 | Review of 28 articles between 1956 and 1968 on brain stimulation and ablation effects on predatory aggression | Imipramine suppresses muricide through its action on the centromedial amygdala; the dose of imipramine required for suppression of muricide is doubled after deafferentiation of the olfactory bulb. |
Da Vanzo 1969 | Review of 11 articles between 1942 and 1967 on drug effects on isolation-induced aggression | Amitriptyline and desmethylimipramine decrease isolation-induced aggression. This effect is potentiated with concurrent scopolamine administration. |
Randrup and Munkvad 1969a Kršiak 1974b | Review of over 200 animal articles between 1923 and 1973 on the pharmacology of aggression; focus is on mouse aggression and stereotyped hyperactivity and "rage" | Imipramine inhibits shock-induced and isolation-induced fighting. Pretreatment with MAOI's plus tricyclics produce vocalizations and boxing postures. |
Carlini et al. 1976 | Review of 80 articles between 1964 and 1975 on drug and environmental factors in marihuana effects | Nomifensine induces aggression in 3 day REM sleep deprived animals. |
Miczek and Barry 1976 Miczek 1987 Miczek and Donat 1989 | Review of over 1500 animal articles between 1920 and 1989 on the pharmacology of sex and aggression | Imipramine decreases intraspecies aggressive behavior at high doses which also impair motor activity. Imipramine decreases killing and can increase aggressive activities in footshock and drug-induced paradigms, but the interpretation is problematic. |
Pinder et al. 1977 Malick 1979 | Review of over 125 animal and human articles between 1942 and 1977 on the pharmacology of aggression; focus is on maprotiline and isolation-induced aggression | Isolation-induced fighting is selectively antagonized with antidepressants (including amitriptyline, desipramine, doxepine, imipramine and maprotiline) at doses not producing neurological impairment. |
Sheard 1977a Eichelman 1979 Maj 1980 Sheard 1981 | Review of over 200 animal articles between 1928 and 1980 on animal models of aggressive behavior | Chronic administration of imipramine, amitriptyline, desipramine, mianserin and iprindole facilitate shock-, apomorphine- and clonidine-induced aggression by prolonging the action of NE in the synapse. |
Delini-Stula and Vassout 1979 | Review of 51 articles between 1956 and 1978 on the effects of psychoactive drugs on aggressive behavior in mice and rats | Predatory, but not shock-induced aggression appears to be consistently inhibited by antidepressants. Amitriptyline and maprotiline suppress isolation-induced aggression. |
References | Methods and Procedures | Results and Conclusions |
B. SEROTONERGIC REUPTAKE BLOCKERS |
| |
Isolation-induced aggression |
|
|
Ogren et al. 1980 | Male albino mice; one subject drug treated | 5 mg/kg i.p. zimelidine inhibits aggressive behavior by 60% for up to 4 hours. |
Delini-Stula and Vassout 1981 | Male albino NMRI mice; acute and 21 day treatment; both subjects drug treated | Acute administration of 10, 25 mg/kg i.p. clomipramine did not affect aggression. Chronic treatment with 10 mg/kg clomipramine decreased the proportion of animals fighting by 40%. |
Poshivalov 1981 | Male CC57W mice with or without 10 mg/kg i.p. l-DOPA or 500 mg/kg i.p. PCPA pretreatment; one subject drug treated | 10 mg/kg i.p. fluoxetine decreased aggressive, social and sexual behavior while increasing defensive behavior. After PCPA or l-DOPA pretreatment, 10 or 20 mg/kg fluoxetine (respectively) decreased aggressive, social and defensive behavior. |
Olivier and van Dalen 1982 | Male mice; one subject drug treated | 25–50 mg/kg i.p. fluvoxamine and chlorimipramine decreased aggressive and increased defensive behaviors. |
Oehler et al. 1985b | Male albino AB/Jena mice; 3 point scale | 20 day administration of 5 mg/kg (in water supply) clomipramine had no effect on aggressivity. |
Pain-induced aggression and defense |
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|
Sheard et al. 1977 | Footshock to pairs of male albino Sprague-Dawley rats treated with 30 ug/kg i.p. LSD; both subjects drug treated | 5 mg/kg i.p. chlorimipramine pretreatment antagonized LSD-enhanced fighting while having no effect on fighting without LSD. |
Marini et al. 1979 | Footshocks to pairs of male albino Sprague-Dawley rats; both subjects drug treated | 2.5, 5 mg/kg i.p. chlorimipramine produced a nonsignificant decrease in fighting. |
Rolinski and Herbut 1981 | Footshock to pairs of male Swiss mice; both subjects drug treated | 0.75, 1.25 mg/kg i.p. fluoxetine dose dependently decreased fighting episodes with a 15–26% decrease in locomotion. |
Valdman and Poshivalov 1986 | Footshock to pairs of male CC57W mice; 7 day pretreatment with 0.5 mg/kg i.p. b.i.d. reserpine; both subjects drug treated | 7 day administration of 10 mg/kg i.p. chlorimipramine or zimelidine reduced timid-defensive and restored aggressive behavior due to nociceptive stimulation. |
Vogel et al. 1988 | Neonatal administration of 15 mg/kg s.c. b.i.d. clomipramine (given from postnatal days 8–21), subsequently, footshocks to pairs of adult male Sprague-Dawley rats; one subject drug treated | Clomipramine treated subjects displayed fewer offensive (offensive uprights, lateral crouch, mounting, leaps toward other subject in response to shock) and more defensive responses (defensive uprights, freezing crouch, supine) than control subjects. |
Defensive aggression induced by brain stimulation |
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|
Dubinsky et al. 1973 | Hissing response and attack behavior via electrical stimulation of the perifornical region of the hypothalamus in male and female cats | Chlorimipramine (ED50:3.4 mg/kg i.p.) decreased attacks with inconsistent effects on the hissing response. |
Drug-induced aggression |
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|
Schrold 1970 | Pairs of 3–10 day old female White-Leghorn or male New Hampshire chicks; both subjects drug treated | 5, 10 mg/kg i.p. chlorimipramine produced a moderate increase in pecking. |
Maj et al. 1979 | Pairs of male Wistar rats treated with 5 mg/kg s.c. apomorphine | 14 day pretreatment with 10 mg/kg s.c. clomipramine produced a 60% increase in the proportion of apomorphine-induced fighting pairs. |
Maj et al. 1981 | Groups of four male albino Swiss mice treated with 20 mg/kg clonidine i.p. | 10 mg/kg i.p. fluoxetine and zimelidine attenuated clonidine induced aggressiveness. Clonidine induced aggressiveness was enhanced 2, but not 72 hours after chronic administration of zimelidine, but not by fluoxetine (10 mg/kg i.p. b.i.d. for 10 days). |
Aggression induced by REM sleep deprivation |
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|
Carlini and Lindsey 1982 | Male albino Wistar rats undergoing 72 hour REM sleep deprivation followed by 2.5, 5 mg/kg i.p. THC; both subjects drug treated | 10, 20 mg/kg i.p. fluoxetine produced aggressive behavior in non-THC treated rats. 5 mg/kg fluoxetine potentiated aggressiveness in THC-treated rats. |
References | Methods and Procedures | Results and Conclusions |
Female aggression |
|
|
Haug et al. 1990 | Groups of 4 female Swiss albino mice: 3 drug treated littermates and 1 untreated lactating dam | 2–8 mg/kg i.p. fluoxetine produced no effect on biting attacks or attack latency. |
Killing |
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Marks et al. 1978 | Muricide and lesions of ascending 5HT projections (dorsal and median raphe nuclei) in adult male Wistar rats | 10–25 mg/kg i.p. chlorimipramine dose dependently inhibited muricide in non-lesioned rats but produced only modest suppression of muricide in lesioned rats without motor impairment. |
Yamamoto and Ueki 1978 Shibata et al. 1984 | Muricide in adult male Wistar King A rats with midbrain raphe lesions or olfactory bulbectomies; acute and chronic (up to 21 day) administration | Chlorimipramine suppressed muricide in raphe lesioned (ED50:10.0 mg/kg i.p.) and OB (ED50:27.5 mg/kg) rats. 20 mg/kg s.c. chlorimipramine decreased muricide by 50% with slight tolerance. |
Fujiwara et al. 1980 | Muricide induced by chronic D9-THC administration in Male Wistar King A rats | 5–20 mg/kg i.p. chlorimipramine dose dependently decreased muricide. |
Schmidt 1980 Schmidt and Meierl 1980 | Rat killing behavior in male ferrets | 15 mg/kg p.o. chlorimipramine and 6, 10 mg/kg p.o. fluoxetine produced no effects on capture elicitation and attack. |
Berzsenyi et al. 1983 Kostowski et al. 1984 Molina et al. 1987 | Muricidal behavior in male Wistar rats treated with 2–3 150 mg/kg p.o. PCPA pretreatments or raphe lesions | 2.5–28 mg/kg i.p. fluoxetine, 2.5–12.5 mg/kg i.p. citalopram dose dependently decreased muricide with minimal effects on motor activity in intact, PCPA treated and raphe lesioned rats. Anti-muricide effects were greater in PCPA treated animals. |
Al-Khatib et al. 1987 | Muricidal behavior in adult male Wistar King-A rats with lesions of the nucleus accumbens | 15 mg/kg i.p. zimelidine suppressed muricide. |
Literature Reviews |
|
|
Sheard 1977a | Review of 119 animal articles between 1928 and 1977 on animal models of aggressive behavior | Chlorimipramine has no effect on shock-elicited fighting, but antagonizes LSD-potentiation of shock-elicited fighting. |
Eichelman 1979 | Review of 177 articles between 1953 and 1979 on the role of the biogenic amines and aggressive behavior | Tricyclic antidepressants block muricide by blocking 5-HT reuptake or degradation. Chronic administration of antidepressants increases shock-induced fighting. |
Malick 1979 | Review of 49 articles between 1942 and 1977 on the pharmacology of isolation-induced aggression in mice | Isolation-induced fighting is selectively antagonized with chlorimipramine at doses not producing neurological impairment. |
Maj 1980 | Review of 68 articles between 1970 and 1980 on the action of antidepressants | Chronic administration of chlorimipramine enhance aggressiveness induced by apomorphine. |
Miczek 1987 Miczek and Donat 1989 | Review of over 1500 articles between 1920 and 1988 on the pharmacology of aggression | Tricyclic antidepressants decrease isolation-induced and predatory aggression. Inconsistent effects are observed with acute administration while chronic administration increases shock-induced aggression. |
C. MONOAMINE OXIDASE INHIBITORS (MAOI) |
| |
Isolation-induced aggression |
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|
DaVanzo et al. 1966 | Male C57B1/10J and ICR mice; one subject drug treated | Phenelzine sulfate (ED50:33.4 mg/kg i.p.), isocarboxazid (ED50:43.5 mg/kg i.p.) and etryptamine (ED50:8 mg/kg i.p.) decreased fighting without affecting motor behavior. |
Valzelli et al. 1967 | Groups of 3 male Swiss albino mice; all subjects drug treated; 5 point aggression scale | 20 mg/kg i.p. phenelzine did not inhibit aggression. 5, 10 mg/kg i.p. pheniprazine and 5–15 mg/kg i.p. tranylcypromine inhibited aggression in 50% of the subjects. |
Welch and Welch 1968b | Male Swiss mice; both subjects drug treated | 50 mg/kg i.p. pargyline increased biting contacts, whole brain NE (22%), DA (35%) and 5-HT (17%); 100 mg/kg decreased biting contacts. |
Pain-induced aggression and defense |
|
|
Tedeschi et al. 1969 | Footshock to pairs of male mice; both subjects drug treated | 200 mg/kg i.p. iproniazid increased fighting without affecting motor behavior. |
References | Methods and Procedures | Results and Conclusions |
Eichelman and Barchas 1975 | Footshocks to pairs of male Sprague-Dawley rats; both subjects drug treated | 3–5 day administration of 100 mg/kg nialamide i.p., 150 mg/kg i.p. iproniazid or 20 mg/kg i.p. pargyline potentiated attacks without altering pain thresholds. |
Rolinski and Herbut 1981 | Footshock to pairs of male Swiss mice; both subjects drug treated | 30 mg/kg pargyline increased the number of fighting episodes. |
Valdman and Poshivalov 1986 | Footshock to pairs of male CC57W mice; 7 day pretreatment with 0.5 mg/kg i.p. b.i.d. reserpine; both subjects drug treated | 7 day administration of 10 mg/kg i.p. pyrazidol reduced timid-defensive and restored aggressive behavior. |
Defensive aggression induced by brain stimulation |
|
|
Malick 1970 | Hissing response via electrical stimulation of the perifornical region of the hypothalamus in cats | 4–10 mg/kg i.p. tranylcypromine increased behavioral ''irritability" and decreased the threshold to elicit the hissing response. 50–125 mg/kg i.p. pargyline and 5–20 mg/kg i.p. phenelzine increased "irritability" but failed to consistently decrease hiss threshold. |
Lesion-induced aggression |
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|
Malick et al. 1969 | Biting of an inanimate object in male Long-Evans hooded rats with lesions of the septum, ventral-medial hypothalamus or olfactory bulbs | Pargyline decreased aggression in septal (ED50:52.2 mg/kg i.p.), VMH (ED50:193.7 mg/kg) and OB (ED50:139.2 mg/kg) rats. Phenelzine decreased aggression in septal (ED50:40.2 mg/kg i.p.), VMH (ED50:180.7 mg/kg) and OB (ED50:38.2 mg/kg) rats. Tranylcypromine decreased aggression in septal (ED50:5.8 mg/kg i.p.), but not in VMH or OB rats. |
Drug-induced aggression |
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|
Scheel-Kruger and Randrup 1968 | Pairs of male Wistar rats administered pargyline with or without disodium diethyldithiocarbamate (DDC) pretreatment; both subjects drug treated | 150 mg/kg s.c. pargyline produced defensive aggressive behavior in rats receiving DDC pretreatment. DDC and pargyline reduced brain NE and normetanephrine. |
Fog 1969 | Groups of four male albino Wistar rats; all subjects drug treated | 200 mg/kg s.c. pargyline failed to induce vocalizations and defense postures. |
Reis et al. 1970 | Male and female mongrel cats with or without 20 mg/kg i.p. l-DOPA | 20 mg/kg i.p. pheniprazine produced no effect on aggressive behavior. |
Yen et al. 1970 | Biting of an inanimate object in male ICR mice after administration of 500 mg/kg i.v. dl-DOPA | 100 mg/kg i.p. iproniazid and 3–6 mg/kg i.p. tranylcypromine increased the intensity and duration of DOPA-induced biting. |
Zetler and Hauer 1975 | Vocalizations and biting of an inanimate object in male Wistar rats | 30 mg/kg i.p. isocarboxazid increased vocalizations and attacks. |
Rolinski and Herbut 1979 | Pairs of male Wistar rats treated with 20 mg/kg apomorphine; both subjects drug treated | 50 mg/kg i.p. pargyline suppressed aggressive behavior. |
Aggression by resident toward intruder |
|
|
Avis and Peeke 1979 | Male convict cichlids (Cichlasoma nigrofasciatum); resident drug treated | 5, 10 mg/L (in aquarium water) pargyline dose dependently decreased attack displays. |
Payne et al. 1985 | Male hamsters; resident drug treated | 70 mg/kg i.p. pargyline decreased attacks and increased attack latency. |
Killing |
|
|
Horovitz et al. 1965 Horovitz et al. 1966 Hitchens et al. 1972 | Muricidal behavior in female Holtzman rats | Iproniazid (ED50:155 mg/kg i.p.) and phenelzine (ED50:5 mg/kg i.p.) inhibited muricide with minimal effects on motor coordination. |
Sofia 1969a | Muricidal behavior in male hooded Long-Evans rats | Pargyline (ED50:127.6 mg/kg i.p.), tranylcypromine (ED50:4.1 mg/kg i.p.), etryptamine (ED50:9.77 mg/kg i.p.), nialamide (ED50:158.9 mg/kg i.p.), isocarboxazid (ED50:28.7 mg/kg i.p.) and phenelzine (ED50:28.0 mg/kg i.p.) decreased muricide. Iproniazid (ED50:216.9 mg/kg i.p.) decreased muricide at neurotoxic doses. |
Leaf et al. 1978 | Muricidal behavior in adult male and female cats | 0.25–1 mg/kg i.p. tranylcypromine did not inhibit muricide. |
Watanabe et al. 1979 | Muricidal behavior in male Wistar King A rats with olfactory bulbectomies | Bilateral injection of 100 ug nialamide into the medial, basal or anterior amygdala, lateral septum or ventral hippocampus did not inhibit muricide. |
References | Methods and Procedures | Results and Conclusions |
Isel et al. 1988 Isel and Mandel 1989 | Muricidal behavior in male Wistar rats with or without 2 day 150 mg/kg i.p. PCPA treatment or raphe lesions | 18.6, 37.2 mg/kg i.p. moclobemide moderately decreased muricide while decreasing motor activity in intact, PCPA treated and raphe lesioned rats. 5.0–11.8 mg/kg i.p. cimoxatone, 24.2–72.5 mg/kg i.p. toloxatone, 3–10 mg/kg i.p. minaprine dose dependently decreased muricide with minimal effects on locomotor activity in intact, PCPA treated and raphe lesioned rats. |
Literature Reviews |
|
|
Valzelli 1967 | Review of over 200 articles between 1934 and 1966 on drugs and aggressiveness | MAOI's (iproniazid, phenelzine and pheniprazine) increase aggression in isolation-, shock-induced and muricide paradigms. |
Randrup and Munkvad 1969a | Review of 80 animal articles between 1923 and 1969 on the mechanisms involved in stereotyped hyperactivity and "rage" | MAOI's with and without DOPA produce aggression in pairs of rats and mice and may be related to NE effects. |
Welch and Welch 1969a Welch and Welch 1973 Malick 1979 | Review of over 60 animal articles between 1942 and 1977 on aggression and the biogenic amines | MAOI's (pargyline, pheniprazine, isocarboxazid, etryptamine and phenelzine) decreases isolation-induced aggression without producing neurological impairment by accelerating the release of NE, DA and 5HT. However, low doses may enhance fighting for a short period of time. |
Kršiak 1974b Sheard 1977a Eichelman 1979 Sheard 1981 | Review of over 200 animal articles between 1928 and 1979 on the pharmacology of aggression | MAOI's increase shock-elicited fighting and decrease muricide. MAOI's plus tricyclics or adrenergic compounds produce vocalizations and boxing postures. |
Miczek 1987 Miczek and Donat 1989 | Review of over 1500 articles between 1920 and 1989 on the pharmacology of aggression | MAOI's decrease isolation-induced and predatory aggression. Acute and chronic MAOI's decrease and increase shock-induced aggression, respectively. |
Table 8B: Effects of Antidepressant Drugs on Aggression in Humans
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
A. NORADRENERGIC REUPTAKE BLOCKERS |
| |
Behavioral disorders in juveniles |
|
|
Winsberg et al. 1972 | 32 male and female hyperkinetic and aggressive children (age: 5.3–13.6 years) in New York; 39-item behavior rating scale; double-blind, placebo control | 50 mg p.o. t.i.d. imipramine decreased aggressivity, hyperactivity and inattention in 69% of the patients compared to 44% of the patients receiving 5–10 mg p.o. t.i.d. d-amphetamine. Cognitive impairment was not observed. |
Rapoport et al. 1974 | Conners rating scale, diary evaluation, and psychiatric evaluation of 76 male hyperactive (age: 6–12 years) outpatients; double-blind, placebo control | 80 mg/day imipramine decreased hyperactivity and produced cognitive improvement in the most inhibited, anxious children. Unusually aggressive children showed no improvement. Side effects included sedation, irritability, insomnia, decreased appetite, nausea, sadness and increased blood pressure. |
Waizer et al. 1974 | Psychiatric and psychological evaluation of 19 male hyperactive children (age: 6–12 years) in New York; placebo control | 50–75 mg t.i.d. imipramine reduced hyperactivity, defiance and inattentiveness and increased sociability. Side effects included anorexia and insomnia but "represented no serious problem." |
Yepes et al. 1977 | BRS, teacher and parent rating of 21 male and 1 female (mean age: 9.2 years) aggressive or hyperkinetic outpatients; double-blind, placebo control | 17–50 mg p.o. t.i.d. amitriptyline decreased hyperactivity, aggression and produced sedation. This was comparable to 10–30 mg p.o. b.i.d. methylphenidate without producing cognitive impairment. |
Pallmeyer and Petti 1979 | 2 male patients (age: 6, 12 years) with childhood depression in Pittsburgh | 3.5–5 mg/kg p.o. daily imipramine markedly increased aggressive and hostile behavior which subsided with discontinuation. |
Puig-Antich 1982 | Unstructured observations and K-SADS-P administered to 43 prepubertal male patients (mean age: 9.6 years) with major depression including conduct disorder; open trials and double-blind, placebo control | 5–13 week treatment with 5 mg/kg/day imipramine improved affect followed by an abatement of conduct disorder. |
Inpatient studies |
|
|
Wood et al. 1976 | MMPI, WRAT and WAIS and self-evaluation in 15 male and female patients (mean age: 28 years) with minimal brain dysfunction; comparison of methylphenidate, pemoline and imipramine; open trial | One patient not responding favorably to methylphenidate or pemoline became less anxious, irritable and angry with 10 mg/day imipramine. Adults with minimal brain dysfunction manifested the same response to medication as do children. |
Rampling 1978 | Tricyclic-induced aggressiveness in 3 male and 1 female patients (age: 26–52 years) in Australia | Untoward immediate aggressiveness was a rare (possibly underreported) side effect of tricyclics (25 mg b.i.d. imipramine, 25 mg t.i.d. and 150 mg h.s. amitriptyline). |
George et al. 1989 | 3 male and female patients (age: 28–32 years) with aggressive behavior and panic disorder | 100 mg daily desipramine or 200 mg daily imipramine for panic disorder reduced anger, rage and assaultive behavior. |
Outpatient studies |
|
|
Panter 1977 | Untreatable, verbally and physically assaultive 30 year old female in California | 200 mg daily doxepine produced no clear improvement of impulsive and dangerous behavior. |
Experimental studies |
|
|
Overall et al. 1964 | BPRS, IMPS and MMPI administered to 68 male schizophrenic and 77 male depressive patients (age: 25–76 years); double blind | 240 mg p.o. daily imipramine produced minimal or no improvement on hostility and uncooperativeness in schizophrenic and depressive patients. |
Gottschalk et al. 1965 | Analysis of speech for hostility in 5 patients (age: 16–52); single and double blind, placebo control | 50–200 mg p.o. q.i.d. imipramine increased verbal overt outward hostility and anxiety scores. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Itil et al. 1972 | Clinical Global Score, HZI Depression, Hamilton Anxiety, anxiety self-rating and psychosomatic rating scales administered to 25 male and female mild to moderate depressive outpatients; double-blind, placebo control | Daily administration of 60–200 mg p.o. amitriptyline or 20–72 mg p.o. mianserin decreased anxiety and irritability which was maximal after 3 weeks; mianserin produced no side effects except for slight sedation. |
Literature Reviews |
|
|
Itil and Seaman 1978 Miczek 1987 | Review of over 1500 articles between 1920 and 1987 on the pharmacology of aggression | Antidepressants are ineffective or inconsistent in the treatment of aggression in adults. In hyperactive children, imipramine and amitriptyline can reduce hyperactivity but not always conduct disorders. |
Gunn 1979 Tupin 1985 | Review of over 35 articles between 1967 and 1985 on the psychopharmacology of aggression | Antidepressants (imipramine, amitriptyline) produce a 60–70% remission of violent outbursts in depressed patients; there are some reports of paradoxical rage. |
B. SEROTONERGIC REUPTAKE BLOCKERS |
| |
Outpatient studies |
|
|
Yaryura-Tobias and Naziroglu 1978 | 12 female outpatients (age: 14–39 years) with obsessive-compulsive, aggressive and self-mutilating behavior in New York | 260 mg p.o. daily chlorimipramine decreased obsessive-compulsive symptoms, aggression and self-mutilation in 75% of the patients; 25% worsened and were diagnosed as schizophrenic. |
Literature Reviews |
|
|
Rapoport 1989 | Review of clomipramine and obsessive-compulsive disorder | 4% of obsessive-compulsive patients have aggressive thoughts; clomipramine appears to have selective anti-obsessive-compulsive properties. |
Table 9A: Effects of Lithium on Aggression in Animals
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Isolation-induced Aggression |
|
|
Weischer 1969 | Male albino NMRI mice; one subject drug treated | 30 mEq/L lithium (in drinking water) decreased aggression after 2–3 weeks in 35% of the animals with a 14% mortality rate. |
Brain 1972 | Male albino mice; one subject drug treated | Daily intake of 4.83 ml (0.9%) lithium chloride (in drinking water) for 15 days decreased fighting duration and number of attacks, this corresponded to an increase in adrenocortical and a decrease in gonadal function. |
Eichelman et al. 1977 | Male CF1 mice; both subjects drug treated | 14 day administration of 1.5–6.0 mEq/kg i.p. b.i.d. lithium dose dependently decreased fight duration. |
Malick 1978b | Male CF1-S mice; both subjects drug treated | Acute administration of 40–300 mg/kg i.p. lithium did not inhibit the proportion of animals fighting. 5 day repeated administration of 40–300 mg/kg lithium dose-dependently decreased fighting. |
Brain and Al-Maliki 1979 | Male albino TO mice; one subject drug treated | 0.2, 0.4 mEq i.p. lithium decreased the proportion of animals fighting, attacks, attack duration and increased the attack latency. |
Grimm and Zelikovich 1982 | Male SJL/J mice; one subject drug treated | Acute administration of 5 mEq/kg i.p. lithium eliminated attacks and nonaggressive social behavior in 40% of the subjects; 4 day administration of 5 mEq/kg lithium eliminated attacks and nonaggressive social behavior in 80% of the subjects. |
Oehler et al. 1985b | Male albino AB/Jena mice; 3 point scale | 20 day administration of 4 nmol/kg (in water supply) lithium decreased attacks. |
Pain-induced aggression and defense |
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Sheard 1970b | Footshock to pairs of Sprague-Dawley rats; both subjects drug treated | 5 mEq/kg i.p. lithium for 5 days increased attack latency and shock level sustained without fighting and did not alter the pain threshold. Polydipsia noted. |
Bisbee and Cahoon 1973 | Footshock to male Sprague-Dawley rats; inanimate bite target | 3.2–12.7 mg/kg i.p. lithium produced no effect on biting when there was no shock delivery. When shock administered, 3.2 mg/kg lithium increased and 9.5, 12.7 mg/kg decreased biting. |
Marini et al. 1979 | Footshock to pairs of male albino Sprague-Dawley rats; both subjects drug treated | 20–60 mEq/kg (in food supply) lithium decreased fighting; lithium antagonized 20, 40 ug/kg i.p. LSD-induced increases and 2.5, 5 mg/kg i.p. chlorimipramine-induced decreases in fighting. |
Mukhurjee and Pradhan 1976a | Footshock to pairs of male Walter Reed rats; both subjects drug treated; 3 point scale | 1–3 mEq/kg i.p. once a week lithium dose dependently decreased attacks for up to 48 hours. 3 mEq/kg lithium antagonized d-amphetamine-induced increases and scopolamine-induced decreases in fighting. |
McGlone et al. 1980 | Footshock to male and female Sprague-Dawley rats with lesions to the area postrema; both subjects drug treated | 5 day administration of 5 mEq/kg i.p. lithium increased attack latency (without altering attack frequency) which was abolished with area postrema lesions. |
Brain et al. 1981 | Footshock to pairs of male TO mice; one subject drug treated | 0.2 mEq i.p. lithium produced a nonsignificant decrease in the frequency of attacks. |
Prasad and Sheard 1982 | Footshock to pairs of male Sprague-Dawley rats with and without 14 day treatment with 15 mg/kg i.p. desipramine; both subjects drug treated | 2 week administration of 20 mEq/L lithium (in drinking water) decreased fighting; there was a greater decrease in desipramine-treated rats. |
Drug-induced aggression |
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Delgado and DeFreudis 1969 | EEG recordings and "spontaneous" behavior in restrained adult monkeys (Macaca mulatta) | 50–100 uL i.c. lithium into the amygdala and hippocampus diminished restlessness and aggressiveness in reaction to restraint while producing high voltage, low frequency EEG waves. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Ozawa et al. 1975 | Groups of 4 male ddI mice pretreated with 40 mg/kg nialamide plus 100 mg/kg 1-DOPA or 5–40 mg/kg clonidine; all subjects drug treated | 100, 200 mg/kg lithium potentiated biting attacks in nialamide plus 1-DOPA and clonidine pretreated rats by 200–300% without affecting whole brain NE, DA or 5-HT. |
Allikmets et al. 1979 | 14 day treatment with 1 mg/kg i.p. haloperidol plus 2 mEq/kg i.p. lithium or 2 mEq/kg i.p. lithium to pairs of male Sprague-Dawley rats treated with 5 mg/kg i.p. apomorphine; both subjects drug treated; 4 point aggression scale | Haloperidol potentiated apomorphine-induced stereotypy and aggression which was blocked by concurrent lithium administration. Lithium alone produced no effects on aggression and decreased apomorphine-induced stereotypy. |
Lesion-induced Aggression |
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Mukhurjee and Pradhan 1976b | Hyperexcitability (including biting) in bilateral medial and lateral septal lesioned male Walter Reed and 3 NIH black rats; 4 point scale | 1–3 mEq/kg i.p. once a week lithium dose dependently decreased hyperexcitability; there was an earlier onset and longer duration of action with higher doses. |
Aggression by resident toward intruder |
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Weischer 1969 | (1) Male and female hamsters; resident drug treated. (2) Reactions of Siamese fighting fish (Betta splendens) to intruder or mirror image; resident subject drug treated | (1) 30 mEq/L lithium (in drinking water) decreased aggression after 8–10 days in 55% of the animals. (2) 10–30 mEq/L lithium (in aquarium water) decreased aggression in 25% of the animals for up to 8 hours. |
Sheard 1970a | Male Sprague-Dawley rats in aggressive and sexual interactions with male, female rats or white mice | 5 mg/kg IP lithium for 5 days abolished sexual and aggressive behavior due to subsequent PCPA administration. Forebrain levels of 5HIAA were decreased, there was no change in 5HT. |
Sheard 1973 | Male Sprague-Dawley rats; resident drug treated | 1.5 mEq/L in drinking water for 5 days abolished territorial aggression. |
Female aggression |
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Brain and Al-Maliki 1979 | Introduction of male TO mice to lactating female albino TO mice; female drug treated | 0.2 mEq i.p. lithium did not decrease the proportion of animals fighting, attacks, attack duration or attack latency. |
Killing |
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Krames et al. 1973 O'Boyle et al. 1973 | Muricidal behavior in male Long-Evans and Holtzman rats | Lithium (2% body weight, 0.15 M i.p.) administered immediately, but not at 3 hr, after muricide increased (300%) latency to kill in subsequent encounters. |
Gustavson et al. 1974 | Rabbit and lamb killing in male and female coyotes | 2.5 g i.p. lithium administered after the kill produced sickness and aversion to the eating of prey. After two trials, lithium suppressed attack behavior. |
Rush and Mendels 1975 Broderick and Lynch 1982 | Muricidal behavior in male Sprague-Dawley and Long-Evans rats | Lithium (0.5–12 mEq/kg i.p. or 2 mEq/kg i.p. b.i.d. for 7–10 days) dose dependently decreased muricide in conjunction with increased fore- and hindbrain 5HT turnover. Highest doses impaired motor behavior and were neurotoxic. |
Mukhurjee and Pradhan 1976b | Muricidal behavior in male hooded Long-Evans, NIH black rats and 2 bilaterally septal lesioned male NIH black rats | 1, 2 mEq/kg i.p. once per week lithium had no effect on muricide, 3 mEq/kg i.p. decreased muricide in 30% of the rats. |
Brain and Al-Maliki 1979 | Locust killing in male and female albino TO mice | 0.2 mEq i.p. lithium had no effect on experienced or nonexperienced male or female "killer". |
Klunder and O'Boyle 1979 Langley 1981 | Cricket killing in male ICR or wild northern grasshopper mice | Lithium (0.5–2.0% body weight, 0.15 M i.p.) increased attack latency, suppressed feeding, but did not decrease the killing of live prey. Attack of dead prey was suppressed. |
Yamamoto et al. 1985 | Muricidal behavior in male Wistar King A rats with midbrain raphe lesions or olfactory bulbectomies | Acute administration of 100 mg/kg i.p. lithium suppressed muricide in 25% and 35% of the raphe lesioned and bulbectomized rats, respectively; this suppression increased to 66% and 80% after 5–14 administrations. |
Literature Reviews |
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Sheard 1977a | Review of 119 animal articles between 1928 and 1977 on animal models of aggressive behavior | Lithium dose dependently decreases electrical stimulation-induced aggression. 4–5 week administration of lithium decreases shock elicited fighting. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Malick 1979 | Review of 49 articles between 1942 and 1977 on the pharmacology of isolation-induced aggression in mice | Isolation-induced fighting is selectively antagonized with lithium at doses not producing neurological impairment. |
Svare and Mann 1983 | Review of 41 articles between 1971 and 1982 on hormonal influences on maternal aggression | Lithium produces no effect on postpartum aggression but suppresses intermale aggression in mice. |
Müller-Oerlinghausen 1985 | Review of 40 animal and human articles between 1969 and 1985 on long term lithium treatment | Lithium enhances 1-tryptophan inhibition of muricide. |
Miczek 1987 | Review of over 1500 articles between 1920 and 1987 on the pharmacology of animal and human aggression | Lithium decreases isolation-, shock-, drug- and lesion-induced aggression although higher doses are quite toxic. At nontoxic low doses, enhanced shock- or drug-induced aggression may be seen; lithium is ineffective in decreasing muricide. |
TABLE 9B: Effects of Lithium on Aggression in Humans
References | Methods and Procedures | Results and Conclusions |
Behavioral disorders in juveniles |
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Campbell et al. 1972 | 10 male and female severely hyperactive and severely disturbed children (age: 3–6 years); crossover, double-blind | 0.3–1.2 mEq/L (serum) lithium moderately diminished explosivity, hyperactivity, aggressiveness and psychotic speech while producing nausea and sedation/motor excitation. |
Kelly et al. 1976 | 4 year treatment of a physically and verbally abusive 15 year old mentally handicapped female patient diagnosed with manic-depressive illness | 0.5–1.1 mEq/L (serum) lithium increased the quality of self-control and social behavior with no hypothyroid side effects. |
Platt et al. 1981 Campbell et al. 1982 Platt et al. 1984a,b | DSM3 and cognitive inventories of over 70 male and female treatment-resistant aggressive 5–13 year old inpatients in New York; double-blind, placebo control | 0.32–1.51 mEq/L (serum) lithium was superior to haloperidol and chlorpromazine in decreasing aggressiveness and explosiveness. Cognitive, sedating and insomnia side effects were mild. |
Vetro et al. 1985 | Parent, teacher interviews, hospital records and PFT administration to 17 hyperaggressive male and female children (age: 3–12 years) | 0.68 mmol/L (serum) lithium successfully treated aggressivity in 76% of the patients without sedation or cognitive impairment. Weight gain and gastrointestinal symptoms were present in 41% of the patients. |
Inpatient studies |
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Dostal and Zvolsky 1970 | 14 phenothiazine resistant aggressive and severely mentally handicapped male patients (age: 11–17 years) | 0.3–0.95 mEq/L (serum) lithium reduced aggressiveness and undisciplined behavior in 79% of the patients; unusually severe polydipsia and polyuria present. |
Martorano 1972 | 2 violent male paranoid schizophrenics (ages: 21 and 25 years) | 0.3–0.7 mEq/L (serum) lithium abolished aggressive and acute psychotic reactions within 3 weeks. Affective rage and hyperactivity may be associated with lithium efficacy. |
Tupin 1972 | Untreatable, assaultive and self-injurious behavior in 10 patients; open trials; includes case study of a 26 year old male; diagnoses varied: antisocial personality, mental deficiency, explosive-aggressive personality | Lithium suppressed belligerent angry and self-injurious behavior (with and without an episodic course). |
Micev and Lynch 1974 | 6 male and 4 female, untreatable, aggressive and self-mutilating mentally handicapped inpatients (age: 16–58 years) in the U.K. | 0.6–1.4 mEq/L (serum) lithium modestly to significantly improved aggressive outbursts in 89% of the patients. Self-injurious behavior was abolished in 75% of the patients. |
Shader et al. 1974 | Untreatable, aggressive and assaultive 34 year old female in Massachusetts | 0.6–1.0 mEq/L (serum) lithium decreased impulsiveness, aggressiveness and feelings of anger. |
Lion et al. 1975b | Untreatable, impulsive and assaultive 27 year old mentally handicapped male patient in Maryland | 1.2 mEq/L (serum) lithium reduced agitation, aggressiveness and restlessness. |
Altshuler 1977 | Untreatable, impulsive and aggressive behavior in 9 male and female early total deafness patients (age: 16–52 years) in New York: 6 schizophrenics, 2 acting out adolescents and 1 personality disorder | 0.42–0.8 mEq/L (serum) lithium decreased or completely suppressed violent, impulsive and aggressive behavior in 78% of the patients. There was no improvement in 1 schizophrenic patient and 1 other patient due to malaise. |
Goetzl et al. 1977 | 3 aggressive male and female mentally handicapped patients (age: 16–20 years) in New York | 0.6–0.9 mEq/L (serum) lithium reduced aggressive, hyperactive behavior and increased social behavior. Nausea, vomiting and diarrhea noted in one patient. |
Cutler and Heiser 1978 | 30 year old male with 6 year history of impulsive, violent and assaultive behavior | 0.95 mEq/L (serum) lithium abolished violence and impulsiveness without untoward side effects. |
Dale 1980 | 15 untreatable and violent mentally handicapped male and female inpatients (age: 17–63 years); open trial | 0.4–1.2 mmol/L (serum) lithium reduced aggressive outbursts within 2 weeks in 73% of the patients. No response and a worsening of violence in 3, 1 patients, respectively. One patient developed tardive dyskinesia. |
Sovner and Hurley 1981 | Untreatable, assaultive self-injurious 26 and 44 year old severely mentally handicapped females in Massachusetts | 1–1.35 mEq/L (serum) lithium decreased aggressive and self-injurious behavior while producing polyuria and hypothyroidism. |
References | Methods and Procedures | Results and Conclusions |
Buck and Havey 1986 | Untreatable and violent mentally handicapped 23 year old male inpatient in Maine | 0.8 mEq/L (serum) lithium with 9.5 µg/mL carbamazepine (serum) produced a near complete suppression of violent and schizophrenic behavior. |
Elliott 1986 | Case studies of 2 unmanageable, aggressive mentally handicapped patients (ages: 44 and 22 years) | 0.8–1.0 mEq/L (serum) lithium decreased aggressiveness, temper outbursts and inappropriate sexual behavior in both patients; this was associated with decreased IQ, attentiveness and cognitive abilities. |
Glenn et al. 1989 | Case studies of 5 male and 5 female brain injured inpatients (age: 20–75 years) with unremitting aggressive, combative, self-injurious or severe affective instability | 0.5–1.4 mEq/L (serum) lithium improved aggressive and self-injurious behavior in 70% of the patients. Neurotoxicity demonstrated in 30% of the patients, particularly when used in conjunction with neuroleptics. |
Luchins and Dojka 1989 | Retrospective analysis of aggressive and self-injurious behavior (SIB) of 11 male and female mentally handicapped inpatients (age: 27–55 years) | 0.6–0.95 mEq/L (serum) lithium decreased aggression and SIB in 64% and 82% of the patients, respectively. |
Outpatient studies |
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Panter 1977 | Untreatable, verbally and physically assaultive 30 year old female in California | 1.3–1.5 mEq/L (serum) lithium decreased or suppressed aggressive, assaultive and self-injurious behavior. |
Freinhar and Alvarez 1985 | 29 year old male with bipolar and intermittent explosive disorders, alcohol and cocaine abuse in California | 0.5–0.8 mEq/L (serum) lithium completely suppressed violent behavior and severe mood fluctuations. |
Criminal violence |
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Sheard 1971 | Verbal hostility, physical aggressiveness and self-rating of 12 violent, assaultive male inmates (age: 21–43 years); single-blind, placebo control | 0.6–1.5 mEq/L (serum) lithium decreased rating of aggressive affect and aggressive behavior. Side effects uncommon but included mild nausea, increase in thirst and insomnia. |
Tupin et al. 1973 | Psychiatric and self evaluation, prison records of 27 male convicts exhibiting violent behavior; open trial | 0.82 mEq/L (serum) lithium decreased aggressiveness, prison rule infractions for violence and feelings of aggression in 78% of the inmates. Side effects included nausea, vomiting and tremor; 4 inmates discontinued lithium therapy because of ulcers, leukocytosis and psychosis. |
Kerr 1976 | Untreatable and violent 29 year old mentally handicapped female child batterer in Tasmania | ''Therapeutic dosages" of lithium suppressed irritability and explosive rages; patient in good health after 12 months. |
Marini and Sheard 1976 Marini and Sheard 1977 Sheard et al. 1976 Sheard 1977b Sheard and Marini 1978 | Motor, cognitive and prison records of 66 impulsive aggressive delinquent males (age: 16–24 years); double-blind, placebo control | 0.6–0.9 mEq/L (serum) lithium decreased overt aggression (prison infractions are abolished within 3 months) which was not due to: toxicity, motor impairment, cognitive deficits, hypothyroidism, reduced testosterone or manic-depression. Side effects noted were tremor, dry-mouth, polyuria and nausea. |
Experimental studies |
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Rifkin et al. 1972 | Psychiatric evaluation, Oklahoma Behavior Rating Scale administered to 21 male and female inpatients with emotionally unstable character disorder; crossover double-blind, placebo control | 0.6–1.5 mEq/L (serum) lithium controlled mood swings and "maladaptive behavior patterns," reactivity in 67% of the patients compared to 20% placebo improvement. |
van Putten and Sanders 1975 | Hospital record review and GAS inventory of 35 male and female inpatients with untreatable, intractable mental illness; double-blind, placebo control | 0.7–1.7 mEq/L (serum) lithium decreased agitated depression, mania, and unstable-aggressive behavior in 31% of the patients. |
Worrall et al. 1975 | 8 non-manic depressive assaultive mentally handicapped female inpatients; 7-point aggression scale; double-blind, placebo control | 0.74–1.38 mEq/L (serum) lithium decreased aggressiveness within 2 weeks of administration: 3 improved, 2 showed no change and 2 signs of neurotoxicity (at 1.16–1.38 mEq/L), 1 worsened. Note: Other psychotropic medication was given concurrently. |
Tyrer et al. 1984 | 17 male and 9 female mentally handicapped inpatients (age: 14–50 years) with assaultive histories in the U.K.; 20 point behavioral inventory; double-blind, placebo control | 0.5–0.8 mmol/l (serum) lithium decreased destructiveness, self-assault and aggression in 68% of the patients without side effects. Factors associated with a positive response include female gender, epilepsy, stereotypic behavior, low initial aggressivity and overactivity. |
Craft et al. 1987 | 20 male and 22 female mentally handicapped inpatients (mean age: 33 years) with assaultive histories in the U.K.; 5 point behavioral inventory double-blind, placebo control | 0.7–1.0 mmol/L (serum) lithium decreased aggression scores and aggressive outbursts in 73% of the patients. No change and increased aggression were noted in 17 and 9% of the patients. "Transitory" polydipsia, polyuria, tremor, drowsiness and vomiting were reported in 36% of the patients. |
Literature Reviews |
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Tupin 1972 Shader et al. 1974 Sheard 1975 Marini and Sheard 1977 Sheard 1977b Sheard 1978 Gunn 1979 Lena 1979 Schou 1979 Lion 1981 Sovner and Hurley 1981 Campbell et al. 1982 Jefferson 1982 Sheard 1983 Sheard 1984 Tupin 1985 Mattes 1986 Cherek and Steinberg 1987 Kazdin 1987 Miczek 1987 Wickham and Reed 1987 Yudofsky et al. 1987 Sheard 1988 | Review of over 1500 human and animal articles between 1920 and 1987 on the treatment and pharmacology of aggression | Lithium decreases assaultiveness in normals and in patients suffering from a lack of impulse control (anger, rage and irritability are easily triggered), schizophrenia, personality disorders, self-injurious behavior. It is effective in mentally handicapped children and adults as well as prison populations. Lithium very rarely exacerbates aggressive behavior. Renal, thyroid and cognitive functioning should be considered and monitored. |
Table 10A Effects of Acute Anxiolytics on Animal Aggression
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
A. Benzodiazepine Receptor Agonists |
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Experimenter Provoked Aggression |
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Randall et al. 1960 Randall et al. 1965 | Aggression directed at experimenter in rhesus monkeys, dogs, cats, and septal or cortical-lesioned rats; no assessment of behavioral specificity. | Chlordiazepoxide produced taming effects in rats (11–21 mg/kg), dogs (10 mg/kg), cats (10 mg/kg) and monkeys (1–20 mg/kg); ataxia observed in dogs and at high dose in monkeys. |
Heuschele 1961 | Aggression directed at observer in zoo animals | Chlordiazepoxide prevented aggression in various species of vicious zoo animals [e.g., a lynx (6 mg/kg), dingoes (3 mg/kg), a baboon (13 mg/kg), and a macaque (5 mg/kg)]. |
Heise and Boff 1961 Scheckel and Boff 1968 | Aggression directed at experimenter in cynomolgus monkeys | 1,4-benzodiazepines including chlordiazepoxide (1–5 mg/kg), diazepam (1 mg/kg), or nitrazepam (0.125 mg/kg) prevented aggressive behavior; oxazepam reduced behavior only slightly at the highest dose (40 mg/kg). |
Scheckel and Boff 1966 | Aggression directed at observer in squirrel monkeys | Chlordiazepoxide (1–2 mg/kg) or diazepam (1–2 mg/kg) prevented aggressive behavior. |
Hoffmeister and Wuttke 1969 | Aggression directed at experimenter in cats | Chlordiazepoxide (10 mg/kg p.o.) prevents defensive aggression directed at experimenter approaching cat with leather glove without producing ataxia. |
Bauen and Possanza 1970 | Aggression directed at the experimenter in minks | Diazepam (15 mg/kg), chlordiazepoxide (50 mg/kg) and oxazepam (25 mg/kg) produced taming, and prevented lunges and attacks without producing muscle relaxation. |
Langfeldt and Ursin 1971 | Aggression directed at the experimenter in feral cats | Diazepam (1 mg/kg i.p.) reduced hissing and attack behaviors in response to experimenter's approach, prodding with a pole or handling. |
Tsumagari et al. 1978 | Aggression directed at the experimenter in rhesus monkeys | Diazepam (2.5 mg/kg) and Y-7131 (10 mg/kg) reduced aggressive displays and attacks in monkeys. |
Tompkins et al. 1980 | Aggression directed at experimenter in rhesus monkeys | Diazepam (5–20 mg/kg) dose dependently reduced observer-rated aggressive response to pole prodding; ataxia was observed at higher doses. |
Kalin and Shelton 1989 | Defensive aggression in infant rhesus monkey when approached by experimenter | Diazepam (1 mg/kg) reduced frequency of aggressive vocalizations (e.g., barking) and defensive freezing behavior, but did not alter distress calls (e.g., cooing). |
Blanchard et al. 1989 | Aggression directed at the experimenter in rats | Chlordiazepoxide (10–20 mg/kg), midazolam (5–10 mg/kg), and diazepam (5 mg/kg) reduced viewer rated defensive aggression. Chlordiazepoxide (10 mg/kg) reduced defensive threats, whereas low doses of midazolam (1–5 mg/kg) reduced biting and a high dose (10 mg/kg) reduced jump attacks and defensive threats. |
Isolation-induced aggression |
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Scriabine and Blake 1962 | Aggression in male mice single housed from 24 hours up to 7 weeks | Chlordiazepoxide (5–10 mg/kg, i.p.) dose dependently reduced time spent fighting. Impairment of motor activity occurred at the highest dose only (20 mg/kg). |
DaVanzo et al. 1966 | Aggression in male C57 B1/10J and Dublin (ICR) mice single housed 1–21 days | Chlordiazepoxide (16–35 mg/kg i.p. ED50) reduced fighting in 2 strains of mice 1, 2 and 4 hours post injection; C57 were more sensitive to antiaggressive effects. Sedative effects were observed at same or lower doses than ED50 that reduced aggression. |
Cole and Wolf 1966 | Aggression in male mice single housed for 6 weeks | Chlordiazepoxide (52 mg/kg p.o. ED50) reduced percentage of mice fighting at doses that were substantially lower than those that produced neuromuscular impairment. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Valzelli 1967 | Aggression in male mice single housed for 4 weeks then placed together in novel cage in groups of 3; aggressive behavior evaluated at 0.5, 1, 2, 4, 6, 8, and 24 hours after administration of saline or drug | Chlordiazepoxide (7.5–30 mg/kg i.p.), diazepam (7.5–20 mg/kg i.p.), oxazepam (10–15 mg/kg i.p.), nitrazepam (7.5–30 mg/kg i.p.) reduced viewer-rated aggression scores for 2–6 hours; some evidence of neuromuscular impairment. |
Hoffmeister and Wuttke 1969 | Aggression in male mice single housed for 3–5 weeks; confronts group housed intruder in home cage | Chlordiazepoxide (93.23 mg/kg ED50 p.o.) reduces attack behavior in isolated mice, but sedation is observed at lower doses (33 mg/kg ED50 p.o., in mice climbing an inclined screen) than those that reduced aggression. |
Le Douarec and Broussy 1969 | Isolation-induced aggression in male mice | Chlordiazepoxide (20–40 mg/kg) reduced frequency of attacks by the resident and vocalizations by the intruder; chlordiazepoxide prolonged the intervals between attacks. |
Sofia 1969b | Aggression in pairs of male mice single housed for 8 weeks; confront each other in home cage of one of the isolates | Chlordiazepoxide (23.5 mg/kg i.p. ED50) and diazepam (11.1 mg/kg i.p. ED50) inhibited fighting episodes, but only at doses that were higher than those that altered motor performance (rotorod test). |
Robichaud et al. 1970 | Aggression in pairs of male mice single housed for 3–5 months | Diazepam (6 mg/kg ED50 p.o.), chlordiazepoxide (15 mg/kg ED50 p.o.) and prazepam (27 mg/kg ED50 p.o.) prevented fighting; motor performance on an inclined screen was impaired only at significantly higher doses in female mice tested separately. |
Weischer and Opitz 1972 | Aggression in male mice single housed for 4 weeks | Chlordiazepoxide (10–54 mg/kg, i.p. ED50) produced taming, and muscle relaxation, but did not alter species-specific aggressive behavior. |
Barzaghi et al. 1973 | Aggression in pairs of male mice single housed for 4 weeks | Clobazam or chlordiazepoxide (5–20 mg/kg i.p.) prevented aggressive behavior, but reduced spontaneous motor activity does dependently. However, ataxia (in rotorod test) was only observed at doses 3–5 times higher than those that prevented aggression. |
Valzelli 1973 | Review of references on isolation-induced aggression in male mice | Chlordiazepoxide (10 mg/kg i.p.), oxazepam (10 mg/kg i.p.) and midazolam (10 mg/kg i.p.) inhibited fighting in isolates for 3–5 hours. |
Heilman et al. 1974 | Aggression in male mice single housed for 3 weeks; confronted group housed intruder in neutral cage | Aggression was reduced at high doses of triflubazam (29.5 mg/kg ED 50 i.p.), chlordiazepoxide (28.5 mg/kg ED50 i.p.) and diazepam (14.8 mg/kg ED50 i.p.); motor performance (rotarod test) was impaired at lower doses of diazepam (5.2 mg/kg ED50 p.o.) and triflubazam (15 mg/kg ED50 p.o.) and similar doses of chlordiazepoxide (30 mg/kg ED50 p.o.). |
Ferrini et al. 1974 | Aggression in pairs of male mice isolated for 4 weeks | 10–20 mg/kg i.p. medazepam and SB 5833 reduced observer rated aggression when tested at 1, 2, 4 and 24 hours post injection; temazepam reduced aggression at a lower dose (2.5–5 mg/kg), but muscle relaxation was apparent. |
Fernandez-Tome et al. 1975 | Aggression in pairs of male mice single housed for 4 weeks | Chlordiazepoxide or QM-6008 (10–90 mg/kg p.o.) reduced observer-rated aggression in mice. In separate tests, male mice showed evidence of motor impairment at 60 mg/kg (ED50 i.p.) QM 6008 and at 14 mg/kg (ED50 i.p.) chlordiazepoxide. |
Kršiak 1975a | Aggression in male mice single housed 3–6 weeks | Chlordiazepoxide (5 mg/kg p.o.) increased aggressive threats and attacks; diazepam (1 mg/kg p.o.) did not alter aggressive threats or attacks but did reduce ambivalent behavior (e.g., tail rattle). Other behaviors were unaffected. |
Kršiak 1974a, 1975b | Timidity in male mice single housed 3–6 weeks | Chlordiazepoxide (20–50 mg/kg p.o.) and diazepam (5 mg/kg p.o.) reduced defensive-flight behaviors in timid mice; diazepam increased social behaviors. Walking, rearing and other motor activities were not altered. |
Sulcova et al. 1976 | Timidity in pairs of male mice single housed for 2 weeks | Diazepam (5 mg/kg) inhibited defensive flight behaviors and increased social behaviors without altering motor activities. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Poshivalov 1978 | Timidity and aggression in pairs of male single housed mice | Low doses of medazepam (0.1 mg/kg) increased aggressive behavior in aggressive mice; higher doses of medazepam (5 mg/kg) or diazepam (5 mg/kg) suppressed aggression. |
Malick 1978a | Aggression in pairs of male mice single housed for 4 weeks | Diazepam (10 mg/kg i.p.) reduced percentage of mice that displayed fighting, and produced ataxia. |
Kršiak 1979 | Aggression in male mice single housed for 3–5 weeks | Chlordiazepoxide (50 mg/kg p.o.) and diazepam (10 mg/kg p.o.) reduced attacks and aggressive threats; lower doses of chlordiazepoxide (5 mg/kg) and diazepam (1 mg/kg) reduced ambivalent behavior (e.g., tail rattling). Walking, rearing and other motor activities were unaffected. |
Fielding and Hoffman 1979 | Aggression in male mice single housed for 4 weeks | Clobazam (10 mg/kg ED50 p.o.) and chlordiazepoxide (14 mg/kg ED50 p.o.) reduced percentage of isolated mice exhibiting fighting. Motor performance (rotorod test) was only impaired at substantially higher doses (50 mg/kg p.o. ED50 clobazam) and (30 mg/kg p.o. ED50 chlordiazepoxide) |
Sulcova et al. 1979 Donat and Kršiak 1985 Sulcova and Kršiak 1984, 1986 | Aggression and timidity in pairs of male mice isolated for 3 weeks | Diazepam (3–4 mg/kg p.o.) reduced aggressive threats in aggressive mice and defensive flight behaviors in timid mice without altering motor behaviors; diazepam increased social behaviors in both groups. |
Kršiak et al. 1981 | Aggression or timidity in pairs of male mice single housed for 3–6 weeks | Diazepam (10 mg/kg p.o.) and chlordiazepoxide (50 mg/kg p.o.) reduced attacks in aggressive mice. Diazepam (5 mg/kg) and chlordiazepoxide (20, 50 mg/kg) reduced defense and escape behaviors in timid mice without altering walking or rearing. |
Olivier and van Dalen 1982 | Aggression in male mice single housed for 3 weeks; confronted group housed intruder in neutral cage | Chlordiazepoxide (5–7.5 mg/kg p.o.) increased social, aggressive and defensive behaviors without altering nonsocial behaviors or time spent inactive. |
Sulcova 1985 Sulcova and Kršiak 1989 | Aggression and timidity in pairs of male mice single housed for 3 weeks | At low doses, oral administration of alprazolam (0.05–0.25 mg/kg), oxazepam (2.5 mg/kg), and diazepam (3 mg/kg) reduced defensive behaviors in timid mice; higher doses of alprazolam (1.25 mg/kg), diazepam (10 mg/kg), oxazepam (22.5 mg/kg) reduced attacks without reducing motor activity or social behaviors. Other 1,4 benzodiazepines reduced these behaviors but also produced sedation. |
Grimm and Zelikovich 1982 | Aggression in pairs of male mice single housed for 40 days; prescreened for attack, only more aggressive animals were treated; confronted each other in neutral cage | Diazepam (2.5 mg/kg i.p.) reduced aggression, but also reduced social behaviors. Diazepam-treated animals were attacked by previously submissive untreated opponents. |
Oehler et al. 1985a,b | Aggression in male mice single housed for 3 weeks | Diazepam (4 mg/kg i.p.) produced no changes in aggression or motor behaviors. |
Skolnick et al. 1985 | Aggression in male mice single housed 28 days; confronted group housed intruder in neutral test environment | Diazepam (4 mg/kg s.c.) reduced viewer-rated aggression scores without producing ataxia (rotorod test). |
Beck and Cooper 1986 | Aggression in pairs of male rats single housed for 2 weeks. Pretested for aggression, and more aggressive animal treated; confronted each other in neutral familiar environment | Chlordiazepoxide (5 mg/kg i.p.) increased the duration of aggressive behaviors without altering social or exploratory behavior. |
Poshivalov et al. 1987 | Aggression in pairs of male mice single housed 3–6 weeks | Diazepam (2.5–4 mg/kg) reduced aggressive threats and attacks. |
Plummer and Holt 1987 | Aggression in male rats single housed for 3 weeks; tested in novel environment | Alprazolam (0.5–2 mg/kg), triazolam (0.25–1 mg/kg) reduced aggressive threats and attacks, but bites were increased at the higher doses. Defensive postures were reduced; crouching and freezing increased. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Kršiak and Sulcova 1990 | Aggression and timidity in male mice single housed for 3 weeks; confronted group housed opponent in novel cage | Alprazolam (0.05–2.5 mg/kg p.o.) and oxazepam (2.5–22.5 mg/kg p.o.) reduced attacks in aggressive mice and defensive postures and escapes in timid mice. However, increases in walking were observed in timid animals. Triazolam (0.04–0.75 mg/kg p.o.), nitrazepam (0.25–5 mg/kg), and lorazepam (0.2–1.8 mg/kg) also reduced aggression, but only at doses that altered motor behaviors. |
Pain-induced Aggression and Defense |
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Kostowski 1966 | Electric foot shock-induced aggression in pairs of male mice | Chlordiazepoxide (5 mg/kg i.p.) prevented fighting in mice, but calming and ataxia were observed. |
Hoffmeister and Wuttke 1969 | Electric foot shock-induced aggression in pairs of male mice | Chlordiazepoxide (10 mg/kg ED50 p.o.) reduced aggressive behavior, sedation was observed in mice climbing an inclined screen only at higher doses (33 mg/kg ED50 p.o.). |
Sofia 1969b | Electric foot shock-induced aggression in pairs of male mice | Chlordiazepoxide (4.2 mg/kg i.p. ED50) and diazepam (0.9 mg/kg i.p. ED50) inhibited fighting episodes, at doses that were significantly lower than those that altered motor performance (rotorod test). |
Robichaud et al. 1970 | Electric foot shock-induced aggression in pairs of male mice | Prazepam (13 mg/kg ED50 p.o.) prevented fighting. Motor performance on an inclined screen was impaired at high doses (74 mg/kg ED50) in female mice tested separately. |
Christmas and Maxwell 1970 | Electric foot shock-induced aggression in mice and rats | 1,4-benzodiazepines including chlordiazepoxide (4.7 mg/kg), diazepam (2.1), oxazepam (4.5 mg/kg), and nitrazepam (1.2 mg/kg) reduced percent of animals displaying fighting behaviors in mice and rats at doses well below those that reduced motor activity. |
Irwin et al. 1971 | Electric foot shock-induced aggression in pairs of male mice | Chlordiazepoxide (10–20 mg/kg) reduced leaping and fighting behaviors, but only at doses that reduced muscle tone and produced ataxia. |
Emley and Hutchinson 1971, 1983 | Electric tail shock-induced target biting in male and female squirrel monkeys on a fixed interval schedule | Chlordiazepoxide (1–32 mg/kg s.c.) selectively reduced target biting. At low doses (0.5–8 mg/kg) lever press responding was elevated. Diazepam (0.06–2 mg/kg s.c.) reduced biting nonspecifically as similar doses also reduced lever press responding. |
Manning and Elsmore 1972 | Electric foot shock-induced aggression in pairs of male rats | Chlordiazepoxide (10–40 mg/kg i.p.) dose dependently reduced percentage of fights. Sedation observed at high dose (40 mg/kg). |
Barzaghi et al. 1973 | Electric foot shock-induced aggression in pairs of male mice | Clobazam or chlordiazepoxide (5–20 mg/kg i.p.) reduced the number of fights at doses well below those that reduced motor performance (rotorod test). |
Goldberg et al. 1973 | Electrical foot shock-induced aggression in mice | A low chlordiazepoxide dose (6.4 mg/kg ED50) produced taming and reduced fighting in mice. |
Heilman et al. 1974 | Electric foot shock-induced aggression in pairs of male mice | Triflubazam (9 mg/kg ED50 i.p.), chlordiazepoxide (4.2 mg/kg ED50 i.p.) and diazepam (1.3 mg/kg ED50 i.p.) reduced shock-induced aggression without producing motor impairment (rotorod test, inclined screen, climbing apparatus). |
Quenzer et al 1974 | Electric foot shock-induced aggression in pairs of male rats | Chlordiazepoxide (5–30 mg/kg i.p.) dose dependently reduced shock-induced fighting. Animals were more easily handled, but no noticeable motor deficits were observed. |
Robichaud and Goldberg 1974 | Electric foot shock-induced aggression in pairs of male rats and pairs of male mice | Chlordiazepoxide reduced fighting in mice (6.4 ED50 i.p.) and rats (10 mg/kg MED i.p.); doses that produced muscle relaxation in mice were substantially higher (32.3 mg/kg). Chlordiazepoxide metabolites were not as effective as the parent compound; compounds were effective in the following order: chlordiazepoxide > demethylated chlordiazepoxide > deaminated chlordiazepoxide (demoxepam). |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Kamioka et al. 1977 | Lever response in macaques being threatened by another monkey exposed to electric shock; drugs administered to the aggressor monkey | Oxazepam (2 mg/kg s.c.), cloxazolam (0.5 mg/kg s.c.), chlordiazepoxide (2 mg/kg s.c.), diazepam (0.5 mg/kg s.c.) and CS-386 (0.5 mg/kg s.c.) increased suppressed response in monkeys being threatened by another monkey exposed to electric shock; drugs administered to the aggressor monkey did not increase suppressed response in the monkey being threatened. Some sedation and slight ataxia were observed at highest doses of diazepam and cloxazolam. |
Vassout and Delini-Stula 1977 | Electric foot shock-induced aggression in male rats | Chlordiazepoxide (1–3 mg/kg) did not alter aggression or motor behaviors. |
Tsumagari et al. 1978 | Electric foot shock-induced fighting in mice | Diazepam (1.8 mg/kg ED50 i.p.) and Y-7131 (0.4 mg/kg ED50 i.p.) reduced fighting episodes in mice. Motor activities (rotorod test) were diminished at higher doses of Y-7131 (2.1 mg/kg) and diazepam (5.3 mg/kg). |
Fielding and Hoffman 1979 | Electric foot shock-induced aggression in male mice | Clobazam (2.6 mg/kg ED50 p.o.), chlordiazepoxide (14 mg/kg ED50 p.o) and diazepam (0.16 mg/kg ED50 p.o.) reduced percentage of animals fighting. No motor disturbances for any drug dose <25 mg/kg; ataxia at higher doses. |
Delini-Stula and Vassout 1979 | Electric foot shock-induced aggression in male rats | Diazepam (1–5 mg/kg i.p.) and oxazepam (10–50 mg/kg i.p.) reduced number of fighting bouts; similar doses of both chlordiazepoxide (2.5–10 mg/kg i.p.) and oxazepam (10–25 mg/kg i.p.) reduced locomotor activity. |
Renzi 1982 | Electric tail shock-induced aggression in pairs of restrained male mice tested 6 hours post injection | Chlordiazepoxide (2.5–5 mg/kg,i.p.) did not alter bites. |
Jarvis et al. 1985 | Electric tail shock-induced aggression in pairs of male mice | Chlordiazepoxide (2–16 mg/kg i.p.) dose dependently reduced target biting in confined mice. |
Nakao et al. 1985 | Electric foot shock-induced aggression in pairs of male mice | Diazepam (0.5 mg/kg), carbamazepine (10–20 mg/kg i.p.) reduced shock-induced frequency of fighting bouts; GABA receptor antagonists, picrotoxin (0.3 mg/kg s.c.) and bicuculline (0.5 mg/kg s.c.) blocked this effect. |
Traversa et al. 1985 | Electric foot shock-induced aggression in pairs of male mice | Chlor-desmethyldiazepam (0.04–0.08 mg/kg i.p.) increased shock-induced fighting in mice that showed no fighting in pre-test screening trials; a higher dose (1.25 mg/kg) reduced fighting. |
Aggression Induced by Omission of Reward |
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Miczek 1974 | Aggression in pairs of male rats confronting each other after omission of food reward | Chlordiazepoxide(5–20 mg/kg) produced a biphasic effect on aggression and submissive behaviors. Low doses increased attacks and threats in dominant rats (5 mg/kg), and increased submissive behaviors in intruder males (5–10 mg/kg); the high dose reduced these behaviors. |
Moore et al. 1976 | Extinction-induced aggression directed at a mirror in pigeons | Aggressive mirror response was suppressed by chlordiazepoxide (5 mg/kg), without altering key pecking response. |
Amone and Dantzer 1980 | Extinction-induced aggression in pairs of pigs: Operant behaviour | Diazepam (1–2 mg/kg i.m.) increased the frequency of biting and fighting as well as total duration of aggressive bouts; diazepam reduced plasma cortisol levels that were elevated following extinction. |
Defensive Aggression Induced by Electrical Brain Stimulation |
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Baxter 1964 | Defensive aggression in cats following electrical stimulation in hypothalamus | Chlordiazepoxide (5–20 mg/kg i.p.) produced taming, but did not alter electrical threshold required to elicit hissing. |
Malick 1970 | Defensive aggression in cats following electrical stimulation in hypothalamus | Chlordiazepoxide (10–15 mg/kg i.p.), diazepam (4–7.5 mg/kg i.p.) or oxazepam (12 mg/kg i.p.) elevated the electrical threshold required to elicit hissing. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Funderburk et al. 1970 | Defensive aggression in cats following electrical stimulation in hypothalamus | Chlordiazepoxide )10 mg/kg i.p.) elevated the electrical threshold required to elicit hissing without producing ataxia. |
Otsuke et al. 1973 | Defensive aggression and startle response in cats following electrical brain stimulation in hippocampus, amygdala, ventromedial hypothalamus or midbrain reticular formation | Nitrazepam (1 mg/kg i.p.) reduced hissing and attacks in response to air puffs and pole prodding, but also produced marked ataxia; diazepam (1 mg/kg i.p.) reduced hissing, but did not alter attacks. |
Delgado 1973 | Defensive aggression in male and female rhesus monkeys following electrical brain stimulation in thalamus and central grey | Chlordiazepoxide (8 mg/kg i.m.) prevented defensive aggression (staring, ear flattening, piloerection, barking and attacks) for 6 hours in restrained and free moving animals; chlordiazepoxide (5 mg/kg i.m.) prevented aggression directed at observers or object placed in cage. No noticeable motor deficits were observed. |
Murasaki et al. 1976 | Defensive aggression in cats following electrical stimulation in hypothalamus | Diazepam (1 mg/kg i.p.) elevated electrical threshold required to elicit hissing and further elevated threshold to attack. |
Tsumagari et al. 1978 | Defensive aggression in cats following electrical stimulation in hypothalamus | Diazepam (0.36 mg/kg ED50 p.o.) and Y-71 (0.06 mg/kg ED50 p.o.) reduced rage response in cats. Sedation and ataxia were observed at 0.39 mg/kg p.o. diazepam and at 0.25 mg/kg p.o. Y-7131. |
Kruk et al. 1987 | Aggression in rats following electrical stimulation in hypothalamus | Chlordiazepoxide (5–20 mg/kg p.o.) did not alter threshold for attack or locomotion, but animals shifted to a less violent form of attacks (strong bite to mild bite); oxazepam (5–20 mg/kg p.o.) treated animals displayed a similar shift and a slight increase in attack threshold. |
Polc et al. 1981 | Defensive aggression in cats following electrical stimulation in hypothalamus | Diazepam (1 mg/kg i.p.) elevated the threshold for eliciting attack response; elevations were prevented by Ro 15–1788 (5 mg/kg i.p.). |
Fukuda and Tsumagari 1983 | Defensive aggression in cats following electrical stimulation in hypothalamus | Diazepam (0.25–1 mg/kg i.p.), nitrazepam (0.1–0.2 mg/kg i.p.), and lorazepam (0.05–0.1 mg/kg i.p.) elevated electrical threshold for direct attack dose dependently; hissing threshold was reduced at higher doses of diazepam (1–5 mg/kg). Muscle relaxation observed at 0.48 mg/kg diazepam, 0.61 mg/kg nitrazepam, and 0.14 mg/kg lorazepam (ED50). |
Drug-induced Aggression |
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Yen et al. 1970 | dl-DOPA-induced aggression in mice | Chlordiazepoxide (13 mg/kg ED50), diazepam (2.5 mg/kg ED50), oxazepam (8.8 mg/kg ED50) reduced target biting without producing ataxia. |
Nakamura and Thoenen 1972 | 6-OHDA-induced aggression in rats | Diazepam (1 mg/kg every 2 hours for 6 hours) produced taming and reduced aggression directed at the experimenter. |
Mueller and Nyhan 1982 | Pemoline-induced self-directed biting in rats | Diazepam (5 mg/kg i.p.) tended to reduce licking and self-biting behaviors in a time dependent manner. Slight reductions in locomotor behaviors were observed. |
Brain Lesion-induced Aggression |
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Blyther and Marriott 1969 | Hypothalamic lesion-induced aggression in rats | Chlordiazepoxide (9 mg/kg ED50 i.p.) reduced hyper-reactivity dose dependently. |
Sofia 1969b | Septal lesion-induced aggression in male mice; ''aggressiveness" was measured for attacks on inanimate objects in tail-restrained animal | Chlordiazepoxide (23.8 mg/kg i.p. ED50) and diazepam (17.2 mg/kg i.p. ED50) inhibited viewer-rated "aggression", but only at doses that were 3 and 4 times higher than those that altered motor performance (rotorod test). |
Horovitz et al. 1963 Loizzo and Massotti 1973 | Septal lesion-induced aggression in rats | Chlordiazepoxide (10–20 mg/kg) reduced hyperirritablity (measured as startle response, vocalization, object attacks and bites), but only at doses 2 times higher than those that produced motor deficits in septal rats and in rats tested in a separate experiment (rotorod test). |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Goldberg et al. 1973 | Septal lesion-induced aggression in rats | Chlordiazepoxide (16 mg/kg ED50) reduced attacks at inanimate objects (pencil and glove). |
Fernandez-Tome et al. 1975 | Aggression in septal lesioned rats | Chlordiazepoxide or QM-6008 (10–90 mg/kg i.p.) reduced observer-rated aggression. However, in rats tested under different conditions, QM-6008 (16.3 mg/kg i.p. ED50) and chlordiazepoxide (8.9 mg/kg i.p. ED50) reduced motor performance (rotorod test). |
Aggression by Resident Toward Intruder |
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Le Douarec and Broussy 1969 | Resident-intruder confrontations in male mice | Chlordiazepoxide (10–40 mg/kg) reduced attacks and ambivalent behavior (e.g., tail rattles) directed at untreated intruder. |
Hoffmeister and Wuttke 1969 | Aggression in pairs of cats confronting each other in cage where partition is removed | Chlordiazepoxide (10–20 mg/kg p.o.) does not alter attack behavior in pairs of male cats confronting one another, ataxia observed at high doses (20 mg/kg). |
Olivier and van Dalen 1982 | Resident male rats confront single housed intruder | Chlordiazepoxide (2.5 mg/kg i.p.) increased aggressive threats and attacks without altering time spent inactive; social behavior was slightly enhanced. |
Olivier et al. 1984 | Resident-intruder confrontations in male rats | Chlordiazepoxide (2.5–10 mg/kg) dose dependently reduced aggression and increased social interactions without altering exploratory behaviors or motor activities. |
Miczek 1985 Weerts et al. 1988 Mos et al. 1990 | Resident-intruder confrontations in male rats | Diazepam increased frequency of attacks and threats and duration of aggressive postures at low doses (0.1–1 mg/kg, i.p.) and decreased aggressive behaviors at moderate to high doses (3–17 mg/kg). |
Yoshimura and Ogawa 1984 Yoshimura 1987 | Single housed resident male mice confronts intruder in home cage | Chlordiazepoxide (5–20 mg/kg i.p.) reduced aggressive threats and attack bites in resident males without altering motor behaviors. Chlordiazepoxide-treated intruders received more attacks from untreated residents and displayed less defensive behaviors in a dose dependent manner. |
Gardner and Guy 1984 | Aggression in the social interaction test in male rats | Chlordiazepoxide (2–12 mg/kg), oxazepam 10–20 mg/kg), lorazepam (2 mg/kg) and nitrazepam (0.2–4 mg/kg) reduced composite measures of aggression and increased social behaviors. Locomotor behaviors were unaffected. |
Mos and Olivier 1988 | Dominant and subordinate resident-intruder confrontations in male rats | Chlordiazepoxide (5, 10 mg/kg) increases the duration of aggressive threats and attacks in both residents and the increases were even higher in the subordinate animal. Motor behaviors were not altered. |
File 1982 | Aggression in untreated male rats in an established colony (n=12) directed at a drug-treated male intruder | Chlordiazepoxide (5 mg/kg i.p.) or lorazepam (0.25 mg/kg i.p..) administration in intruder rats did not alter defensive interactions or aggression received from an untreated resident male. |
Dixon 1975 | Aggression in group-housed male mice | Chlordiazepoxide (no dose specified) increased aggression and social interactions, changing the social structure of mice living in territories. |
Zwirner et al. 1975 | Aggression in group-housed male mice | Chlordiazepoxide (3 mg/kg p.o.) increased attacks between group members. Lower doses (0.3–1 mg/kg p.o.) did not alter aggression. No effects on motor activity were observed at any dose tested. |
Female Aggression |
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Olivier et al. 1985 | Maternal aggression in lactating rats | A low dose of chlordiazepoxide (5–10 mg/kg) increased attack bites dependant on baseline levels of aggression without altering time spent inactive. |
Mos et al. 1987 |
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Yoshimura 1987 | Maternal aggression in female mice that confronted male intruder in home cage on 3, 5, 7, 9 and 11 days post parturition | Chlordiazepoxide (10 mg/kg i.p.) increased frequency of attack bites without altering motor behaviors; 5 mg/kg dose did not alter aggression. |
Yoshimura and Ogawa 1989 | Maternal aggression in lactating rats | Chlordiazepoxide (5–15 mg/kg i.p.) produced a biphasic effect on aggression; 10 mg/kg increased bites and 15 mg/kg decreased bites. Locomotor behaviors were not affected. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Mos and Olivier 1989 | Maternal aggression in lactating rats | At low doses, chlordiazepoxide (5–20 mg/kg p.o.), diazepam (1.25–5 mg/kg p.o.), oxazepam (1.25–20 mg/kg i.p.) and alprazolam (1.25 mg/kg i.p.) enhanced aggression. The magnitude of pro-aggressive effects varied with drug. Oxazepam increased more behavioral elements (threats, bites to head and bites to body, total time spent on aggression) over a wider dose range than chlordiazepoxide or diazepam. Only alprazolam (2.5–5 mg/kg i.p.) reduced aggression; possibly due to stronger muscle relaxant properties. |
Olivier et al. 1990 | Maternal aggression in lactating rats | Low doses of chlordiazepoxide (5–10 mg/kg p.o.) and oxazepam (1.25–10 mg/kg p.o.) enhanced aggression and higher doses (20 mg/kg) reduced it. Diazepam (1.25–5 mg/kg i.p.) and alprazolam (1.25–5 mg/kg p.o.) also were similar but increased aggression was observed at a narrower dose range (1.25 mg/kg only). Drugs did not significantly alter exploratory behaviors or time spent inactive, with the exception of reduced exploration with oxazepam (2.5–20 mg/kg). |
Dominance-related Aggression |
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Delgado et al. 1976 | Dominance-related aggression in socially housed rhesus monkeys | Diazepam (0.1–10 mg/kg p.o.) reduced aggressive behaviors initiated by dominants; chlordiazepoxide-treated subordinates received less aggression from untreated dominants. Mobility was reduced at higher doses (3–10 mg/kg) in dominants and at all doses in subordinates. |
Poole 1973 | Dominance-related aggression in pairs of male hamsters | Chlordiazepoxide (50 mg/kg p.o.) reduced incidence of pursuit and attack in dominant animals; chlordiazepoxide-treated subordinate animals showed reductions in defensive behaviors and an increase in social investigation. No adverse effects on mobility or coordination were observed. |
Fielding and Hoffman 1979 | Aggression in pairs of hamsters | Clobazam (30–60 mg/kg ED50 p.o.) administered 1–6 hours prior to testing reduced bites at doses up to 50 mg/kg without producing motor disturbances. Chlordiazepoxide (10 mg/kg) reduced biting 50%, but also produced ataxia. |
Killing |
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Horovitz et al. 1965 | Predatory aggression in rats | Chlordiazepoxide (30 mg/kg ED50) reduced mouse killing, but at doses that were 6 times the dosage that reduced rotorod performance. |
Kostowski 1966 | Predatory aggression in ants | Chlordiazepoxide (0.5 µ/mg) did not alter the number of ants that attacked beetles. |
Sofia 1969a | Predatory aggression in isolated rats selected for mouse-killing behavior | Chlordiazepoxide (20.2 mg/kg i.p. ED50) and diazepam (219.0 mg/kg i.p. ED50) inhibited mouse-killing, but only at doses that were substantially higher than those that altered motor performance (rotorod test). |
Code and Wolf 1970 | Predatory aggression in grasshopper mice | Chlordizzepoxide (15, 27 mg/kg i.p. ED50) at doses that were half the TD50, increased the latency to attack and the duration of fighting in Onychomys torridus mice, but had no effect on aggression in the more aggressive O. leucogaster strain. |
Panksepp 1971 | Predatory aggression in rats following electrical stimulation in hypothalamus | Chlordiazepoxide (5 mg/kg i.p.) reduced affective attack, but not quiet biting attacks (did not attack other rats, bit dead mice) or escape behaviors; sedation was not apparent. |
Langfeldt 1974 | Predatory aggression in cats | Diazepam (1–4 mg/kg) dose dependently prolonged latency to kill by inducing play behavior. |
Quenzer and Feldman 1975 | Predatory aggression in rats | Chlordiazepoxide (25, 50, 75 mg/kg i.p.) suppressed mouse killing. |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Leaf et al. 1975 Leaf et al. 1984 | Predatory aggression in rats | Oxazepam (2.5–80 mg/kg), diazepam (1.25–10 mg/kg) and chlordiazepoxide (2.5–80 mg/kg) increased the percentage of animals displaying mouse killing behavior. |
Valzelli and Bernasconi 1976 | Isolation-induced predatory aggression in rats | When administered with a single electric shock, chlordiazepoxide (10 mg/kg) and medazepam (10 mg/kg) blocked mouse killing behavior in only 33–37% of killer rats. Lorazepam (0.03 mg/kg), diazepam (10 mg/kg), and oxazepam (15 mg/kg) were not effective. |
Vassout and Delini-Stula 1977 | Predatory aggression in normal and bulbectomized rats | Chlordiazepoxide (1–3 mg/kg) did not alter mouse killing behavior. No motor deficits were observed at these doses. |
Apfelbach 1978 | Predatory behavior in ferrets | Chlordiazepoxide (1 mg/kg) increased killing efficiency; shorter latency to attack larger prey (but received more bites) and less bites required to complete kill |
Leaf et al. 1978 | Predatory aggression in cats | Diazepam (4 mg/kg) and chlordiazepoxide (16 mg/kg) did not alter mouse killing. |
Delini-Stula and Vassout 1979 | Predatory aggression in male rats | Diazepam (3–5 mg/kg i.p.) reduced percentage of animals showing mouse killing behavior in killer rats; diazepam (2.5–10 mg/kg i.p.) dose dependently reduced locomotion counts in mice. |
Hirose et al. 1981 | Predatory aggression in rats | Diazepam (11.8 mg/kg ED50) and 45-0088-S (3 mg/mg ED50) reduced mouse killing. |
Kostowski et al. 1983 | Suppression of predatory behavior in rats during continual electrical stimulation in locus coeruleus | Chlordiazepoxide (5 mg/kg i.p.) prevented suppression of mouse killing. |
Kozak et al. 1984 | Suppression of predatory aggression in rats during continual electrical brain stimulation in locus coeruleus | Chlordiazepoxide (5 mg/kg), aprazolam (2.5 mg/kg), 1-pyramidine-piperazine (10 mg/kg) and MJ-13805 (10 mg/kg) reversed suppression of mouse killing. |
Valzelli and Galateo 1984 | Review of isolation-induced and electrical brain stimulation-induced predatory aggression in rats | Chlordiazepoxide (5 mg/kg), 1-pyramidine-piperazine (10 mg/kg), midazolam (10 mg/kg) and diazepam (5 mg/kg) increased muricidal behavior in isolates, and prevented electrical brain stimulation induced suppression of mouse killing. |
Pellis et al. 1988 | Predatory aggression in cats | Oxazepam (1–3 mg/kg) and diazepam (4 mg/kg) reduced the latency to kill and escalated levels of predation from play to killing. |
B. 5-HT1A Receptor Agonists |
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Experimenter Provoked Aggression |
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Tompkins et al. 1980 | Ratings of aggression directed at experimenter in rhesus monkeys | Buspirone (20–160 mg/kg) dose dependently reduced observer-rated aggressive response to pole prodding without producing ataxia. |
Isolation-induced Aggression |
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Valzelli and Galateo 1984 | Review of isolation-induced and electrical brain stimulation-induced predatory aggression in rats | Buspirone (10 mg/kg) increased muricidal behavior in isolates, and prevented electrical brain stimulation induced suppression of mouse killing |
McMillen et al. 1987 | Aggression in male mice single housed in suspended cages for 3 weeks that were trained to attack group housed intruder in 5 daily sessions. 1st test saline trial, followed by drug test (2nd) 30 minutes after | Gepirone (1.25–10 mg/kg i.p.) dose dependently reduced the number of mice displaying fighting behavior without altering motor performance (rotorod test). |
Cutler and Dixon 1988 | Isolation-induced aggression in pairs of male mice | Ipsapirone (0.3–3 mg/kg, i.p.) reduced aggressive behaviors as well as defensive and ambivalent behaviors. No motor deficits observed. |
McMillen et al. 1988 | Aggression in male mice single housed for 3 weeks that were elected for reliable attack in confrontations with group housed mouse in home cage | Buspirone (1.25–10 mg/kg i.p.), and ipsapirone (2.5–10 mg/kg i.p.) reduced the number of mice that attacked. Doses that reduced aggression did not alter ability of treated animals to orient towards the intruder or reduce motor functions in treated group housed mice (rotorod tests). |
REFERENCES | METHODS AND PROCEDURES | RESULTS AND CONCLUSIONS |
Olivier et al. 1989 | Isolation-induced aggression in male mice | Eltoprazine (0.5–20 mg/kg, PO), ipsapirone (0.3–10 mg/kg, IP) and buspirone (0.3–10 mg/kg, IP) reduced a composite measure of aggression; eltoprazine (1–20 mg/kg) increased social interactions. |
Aggression by Resident toward Intruder |
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Olivier et al. 1984 | Resident/intruder confrontations in male rats | Buspirone (2–8 mg/kg) dose dependently reduced aggressive threats and attacks. Avoidance inactivity and exploration behaviors were decreased. |
Killing |
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Kozak et al. 1984 | Suppression of predatory aggression in rats during continual electrical brain stimulation in locus coeruleus | Buspirone (10 mg/kg) reversed suppression of mouse killing. |
C. ß-Noradregergic Blockers |
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Isolation-induced Aggression |
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Delini-Stula and Vassout 1979 | Aggressioniin male mice single housed for 4–8 weeks | (-)-propranolol (10–20 mg/kg i.p.) reduced percentage of mice fighting without reducing locomotor activity. |
Weinstock and Weiss 1980 | Aggression in male mice single housed for 4 weeks that confronted group housed male in novel test chamber for blind observations | (±)-propranolol (1 mg/kg ED50) and pindolol (1 mg/kg ED50) reduced the number of attacks, and (±)-propranolol increased attack latency. (+)-propranolol (20 mg/kg) did not alter aggressive behavior. Doses up to 2 times higher than ED50 for reducing aggression did not alter locomotor activity. Higher doses of (±)-propranolol (5 mg/kg) actually increased activity. Drugs that reduced aggression also blocked 5-HT-incuded head twitching suggesting serotonergic control. |
Aggression by Resident toward Intruder |
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Miczek 1981 Miczek and DeBold 1983 | Resident male mice confronted a group-housed intruder in home cage; either the resident or the intruder was treated. | l-propranolol (10–20 mg/kg) reduced attack and threat behaviors in treated resident mice facing untreated intruders and did not alter defensive behaviors in treated intruders confronting an untreated resident. |
Yoshimura and Ogawa 1985 | Male mice were tested in a resident intruder paradigm for aggression. Either resident or intruder was treated | dl propranolol (5–20 mg/kg), oxprenolol (30–75 mg/kg) and carteolol (30–75 mg/kg) reduced offensive sideways, attack bite and tail rattle in treated residents, but did not alter aggression in treated intruder mice. |
Yoshimura 1987 Yoshimura et al. 1987 | Male mice were tested in a resident-intruder paradigm for aggression. Subjects received 0, 5, 10, 20 mg/kg d, l, or dl propranolol or practolol PO 60 min before testing. | l or dl propranolol suppressed resident aggressive behaviors. The inactive d isomer had no effect. Only the highest dose l-propranolol (20 mg/kg p.o.) suppressed locomotor activity. |
Kennett et al,. 1989 | Social interaction test in pairs of treated rats under low light and familiar conditions | (-)-propranolol (16 mg/kg, s.c.) did not alter social interaction when administered alone, nor did it reverse suppression of social and aggressive behaviors produced by 5-HT1B agonist mCPP (0.5–1 mg/kg, IP). |
Pain-induced Aggression |
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Vassout and Delini-Stula 1977 | Electric foot shock-induced aggression in pairs of male rats | (-)-propranolol (10 mg/kg i.p.) reduced the number of animals displaying fighting behaviors at doses that did not alter motor capacities. (+)-propranolol was without effects. |
Delini-Stula and Vassout 1979 | Electric foot shock-induced aggression in male rats | (-)-propranolol (10–20 mg/kg i.p.) reduced number of fighting bouts without altering locomotor activity. |
Prasad and Sheard 1983b | Electric foot shock-induced aggression in male rats; all subject received desipramine (10 mg/kg i.p.) for 2 days plus dl propranolol (20 mg/kg i.p.) or saline; 2 tests occurred on the 3rd day (preinjection and dl propranolol); rats were retested on the 4th day (no injection) | Preinjection testing on the 3rd day showed an increase in percent fighting in both rats treated with desipramine and rats treated with desipramine plus dl propranolol. In the second test, injection of dl propranolol alone reduced fighting in both groups. |
Lesion-induced Aggression |
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Bainbridge and Greenwood 1971 | Experimenter provoked ''aggression" in septal lesioned rats as measured by viewer-rated aggression scores | dl- and d-propranolol (10–100 mg/kg s.c.) dose dependently reduced aggression scores. Ataxia observed at highest dose (100 mg/kg) in some animals. |
Killing |
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Vassout and Delini-Stula 1977 | Predatory aggression in intact and bulbectomized male rats | (-)-propranolol (10–20 mg/kg i.p.) inhibited mouse killing behavior without reducing motor capacities. |
Delini-Stula and Vassout 1979 | Predatory aggression in male rats | (-)-propranolol (10–20 mg/kg i.p.) reduced percentage of animals showing mouse killing behavior without altering locomotor activities. |
Shibata et al. 1983 | Predatory aggression in olfactory bulbectomized male rats | Systematic administration (10–20 µg/kg s.c.) of ß-blockers, sotalol and propranolol did not alter mouse killing behaviors, or block DMI-suppressed mouse killing. Microinjection of ß-blockers into amygdala (2 µg/2 µl) did not alter mouse killing behavior nor did it alter mouse killing suppressed by DMI (20 µg/2 µl). |
TABLE 10B: Effects of Chronic Anxiolytics on Animal Aggression
References | Methods and Procedures | Results and Conclusions |
A. Benzodiazepine Receptor Agonists |
| |
Isolation-induced Aggression |
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Sulcova et al. 1976 | Timidity in pairs of male mice single housed for 3–5 weeks | Diazepam (5 mg/kg p.o.) inhibited defensive flight behaviors and increased social behaviors. Motor behaviors were not altered. Chronic treatment (5 mg/kg for 8 days) lessened behavioral effects; 2 days after withdrawal, defensive behaviors were not changed. |
Dixon 1982 | Aggression in untreated male mice single housed for three weeks that confronted drug-treated group housed opponent in home cage | Diazepam-treated (0.125 mM in drinking solution x 14 days) intruder males showed reductions in flight behaviors and increases in attacks received from nondrugged isolates |
Malick 1978a | Aggression in pairs of male mice single housed for 4 weeks confronted each other in home cage of 1 animal; both animals were treated | Diazepam (10 mg/kg i.p.) reduced percentage of mice that displayed fighting, and produced ataxia in subsequent inclined screen test; mice became tolerant to ataxic effects following chronic administration (5 days), but reductions in fighting persisted. |
Grimm and Zelikovich 1982 | Aggression in pairs of male mice single housed for 40 days that were prescreened for attack. Only the more aggressive animals were treated; confrontations were in a neutral cage | Diazepam (2.5 mg/kg i.p.) reduced aggression initially and remained low with chronic treatment (7 days) |
Valzelli 1972 | Review of 7 references on isolation-induced aggression in male mice | Chlordiazepoxide (10 mg/kg), oxazepam (10 mg/kg) and midazolam (10 mg/kg) inhibit fighting in isolates for 3–5 hours |
Pain-induced Aggression and Defense |
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Quenzer et al., 1974 | Electrical foot shock-induced aggression in pairs of male rats | Chlordiazepoxide (5–30 mg/kg x 10 days) reduced shock-induced fighting |
Renzi 1982 | Electrical tail shock-induced aggression in restrained mice | Chronic administration of chlordiazepoxide (2.5–5 mg/kg/day for 10 days) induced a dose dependent increase in biting, whereas acute administration of the same doses produced no changes |
Aggression Induced by Omission of Reward |
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Moore et al. 1976 | Extinction-induced aggression directed at a mirror in pigeons | Chlordiazepoxide (5 mg/kg) suppressed aggressive mirror response and remained low during chronic administration (60 days). Key peck responses were not reduced. |
Drug-induced Aggression |
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Kostowski et al. 1986 | Clonidine- or apomorphine-induced aggression in mice and rats | In mice, chronic administration (5 mg/kg/day for 21 days) of diazepam, alprazolam prevented clonidine-induced (10 mg/kg) attack bites and vocalizations, whereas similar administration of adinazolam potentiated these behaviors. In rats, apomorphine-induced (10 mg/kg) aggression was increased only by chronic diazepam treatment |
Aggression by Resident towards an Intruder |
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File and Tucker 1983 | Resident-intruder interactions in male rats | Chronic administration (from day 7–21 postnatally) of lorazepam (0.25–1.25 mg/kg/day) increased submissive behaviors in adult intruder males towards a non-treated resident |
File 1982 | Aggression in untreated male rats in an established colony (n=12) directed at a drug-treated male intruder | 5 days chronic chlordiazepoxide (5 mg/kg/day i.p.) or lorazepam-treated (0.25 mg/kg/day i.p.) intruders received less aggression from residents, and initiated aggressive behaviors towards established residents; intruders displayed less submissive behaviors. |
File 1986b | Resident-intruder confrontations in male rats | When tested 9 days after cessation of drug treatment, chronic (21 days) neonatal administration of clonazepam (1–5 mg/kg/day) increased aggressive behavior in neonatally treated resident males and defensive behaviors in neonatally treated intruder males |
References | Methods and Procedures | Results and Conclusions |
File 1986a | Resident-intruder confrontations in male rats | 14 days after cessation of chronic (21 days) neonatal administration of diazepam (1 mg/kg/day), increased aggressive interactions were seen in resident animals, whereas cessation of chronic lorazepam (2.5 mg/kg/day) increased submissive behaviors directed at the non-treated intruder; intruders neonatally treated with diazepam (10 mg/kg/day) displayed an increase in wrestling with a non-treated resident, whereas neonatal lorazepam resulted in reductions in kicking |
File and Mabbutt 1990 | Aggression in rats single housed for 1 week that confronted group-housed intruder in home cage | Chronic administration of chlordiazepoxide (10 mg/kg/day, i.p. × 4 weeks) did not alter aggression in drug treated residents or intruders |
Guaitani et al. 1971 | Aggression in group-housed and isolated male mice | Chronic administration (2–6 months) of diazepam (1–50 mg/kg/day), N-desmethyldiazepam (50 mg/kg/day), N-methyloxazepam (50 mg/kg/day) and oxazepam (50 mg/kg/day) increased fighting leading to skin lesions and higher rates of mortality |
Fox and Snyder 1969 Fox et al. 1972 | Aggression in group-housed male mice | Mice consuming a diet containing diazepam (0.1 mg/g food), nitrazepam (0.05 mg/g food) or flurazepam (0.2 mg/g food) for 2–16 weeks showed increased inter-group aggression and reduced defensive behaviors; mortality and wounding were increased |
Female Aggression |
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Yoshimura et al., 1987 | Maternal aggression in lactating female mice that confronted male intruder in home cage day 5 post parturition; chronic treatment with chlordiazepoxide (5–10 mg/kg i.p./day) beginning day 3 of cohabitation and terminated postpartum day 3 | Chronic treatment tended to enhance aggression, but not significantly; motor performance was not altered. |
Yoshimura and Ogawa 1989 | Maternal aggression in lactating rats | Chlordiazepoxide (5–10 mg/kg/day × 20–22 days) did not alter aggression |
Killing |
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Quenzer and Feldman 1975 | Predatory aggression in rats | Chlordiazepoxide (25, 50, 75 mg/kg) suppressed mouse killing following acute administration, but this effect diminished with repeated administration (11 days) |
Literature Reviews |
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DiMascio 1973 | Review of 40 references on experiments of aggression in animals and man | Depending on species, tests, dosage and time course, benzodiazepines can reduce or increase aggression. Generally, there are quantitative differences among chlordiazepoxide, diazepam and nitrazepam, but oxazepam appears to be ineffective or produce opposite effects than the other BNZ. |
TABLE 11A: Effects of Acute Anxiolytics on Human Aggression
References | Methods and Procedures | Results and Conclusions |
A. Benzodiazepine Receptor Agonists |
| |
Treatment of Inpatients |
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|
Lion et al. 1975a | Case report on paradoxical rage reaction in a 25 year old male following diazepam (5 mg × 3/day) for 3 days; patient had history of temper outbursts | Patient became increasingly anxious, argued with wife, and attacked her, fracturing her jaw. |
Salzman 1988 | Case study on administration of lorazepam in violent psychotic patients maintained on low doses of haloperidol. | Lorazepam (1–2 mg, i.m.) administered with haloperidol (5 mg) when a patient became disruptive effectively reestablished behavioral control. |
Bond et al. 1989 | Case reports on aggression and violence in 3 mentally retarded patients | Midazolam (5–10 mg) rapidly stopped violent and aggressive symptoms (e.g., agitation, temper tantrums, assault, and self-injurious behaviors). |
Experimental Studies on Aggression |
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McDonald 1967 | 84 paid female college students were assessed with inventory scales for personality and anxiety and grouped according to action and non-action orientation of high and low anxiety; subjects received placebo or diazepam (5 or 10 mg) | Action-oriented subjects showed an increase on the hostility scale (anger) after diazepam; subjects that were more hostile with diazepam were more anxious and depressed pre-drug and increased anger and anxiety post-drug. |
Wilkinson 1985 | 60 male psychology undergraduates grouped as high, medium or low anxiety according to self reported anxiety inventories (A-Trait, A-State, MAACL), received placebo or diazepam (10 mg) and were told they had received a tranquilizer. Subjects were studied in a competitive reaction time task which consists of setting a shock level against an increasingly provocative opponent | Diazepam increased aggression (shock intensity) in the low anxiety group under low provocation and increased measures of depressive affect. In the high anxiety group aggression increased only under high provocation, concurrent with reductions in anxiety. |
Cherek et al. 1987 Cherek et al. 1990 | 9 normal male subjects were evaluated with structured psychiatric interview (SADS-L); subjects were administered placebo or diazepam (2.5–10 mg/70 kg), and completed a competitive response task, POMS and Buss-Durkee Hostility questionnaires. Each subject received each dose 3 times | Diazepam reduced aggressive responding in 7 out of 9 subjects and slightly increased "escape" responding. In 2 subjects, diazepam increased aggressive responding; aggression increases were correlated with high assaultive and hostility scores in Buss-Durkee, but not with POMS. |
Cherek et al., 1991 | 5 normal male subjects were evaluated with a structured psychiatric interview (SADS-L). Subjects received placebo and triazolam (0.125, 0.25 and 0.5 mg/70 kg of body weight) under double blind conditions, and completed a competitive response task, POMS and Buss-Durkee Hostility questionnaires. Triazolam doses were administered 1st in ascending order and then randomly, so that each subject received each dose twice. | Triazolam effects on aggressive responding differed according to scores of hostility and anger; 2 subjects with low Buss-Durkee scores showed decreases, and 2 subjects with high Buss-Durkee scores showed increases. Triazolam reduced reinforced responding and escape responding in all subjects. |
Literature Reviews |
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|
Itil 1981 | Review of 71 references on drug therapy management of aggression | Acute aggressive states associated with organic syndrome, isolated explosive disorders, and alcohol withdrawal, can be controlled with acute intramuscular administration of chlordiazepoxide (up to 100 mg); aggressive syndrome associated with epilepsy is also treatable with benzodiazepines. |
TABLE 11B: Effects of Chronic Anxiolytics on Human Aggression
References | Methods and Procedures | Results and Conclusions |
A. Benzodiazepine Receptor Agonists |
| |
Treatment of Inpatients |
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|
Tobin and Lewis 1960 | 135 women and 77 men with behavioral disturbances including anxiety, phobia, obsessive/compulsive behavior, depression, and hysterical acting-out behavior were administered chlordiazepoxide (25–175 mg/day for 1 week to 13 mo.); subjects were evaluated by physician and interviews during psychotherapy | 18 of 23 patients with hysterical acting-out behavior showed reductions during chlordiazepoxide treatment; acute rage reactions occurred in 3 patients. |
Ingram and Timbury 1960 | 9 outpatients with phobic anxiety and 6 with obsessional neuroses were administered chlordiazepoxide (10–25 mg 3x/day) | Side-effects included hyperactivity in 1 patient, increased irritability in 2 patients and assaultive behavior in 1 patient. |
Boyle and Tobin 1961 | Case reports of 25 behaviorally disruptive patients with chronic brain syndrome, schizophrenia, psychosis or mental retardation | 15 patients showed improvement with chlordiazepoxide treatment (10–500 mg for 4 days-10 mo.); 6 slightly and 8 marked reduction in aggressiveness, agitation, hostility and assaultiveness. One patient showed increased aggressiveness following chlordiazepoxide. |
Murray 1962 | Case history of a psychiatric patient with chronic depressive disorder and anxiety administered chlordiazepoxide (75 mg/day) | Patient's depressive state improved but he also became verbally aggressive and agitated, with numerous behavioral outburst that continued despite lowering of dosage to 25 mg/day |
Feldman 1962 | 55 anergic and hyperanergic patients, 17 patients with depressive reactions, 70 anergic schizophrenics received chlordiazepoxide or diazepam (ED50 20–30 mg/day) | Combativeness, hostility, and hallucinations were unaffected by diazepam, but were reduced by chlordiazepoxide; diazepam relieved hypoactivity, but facilitated assaultive behavior in one patient and feelings of "hate". |
Monroe and Dale 1967 | 10 chronically hospitalized schizophrenic patients; 8 with "activated EEG's" received chlordiazepoxide (20–50 mg 4x/day) was added to drug treatments for month, 1, then chlordiazepoxide was administered alone for month 2, and placebo alone for month 3. If chlordiazepoxide reduced symptoms, it was resumed for month 4 to determine if response could be repeated | 8 of 10 patients that exhibited impulsive acting out behavior (physical attacks, suicide attempts, or inappropriate sexual behavior) showed dramatic improvement or complete disappearance of impulsiveness. 5 out of 10 were more "sociable" and communicative. |
Goddard and Lokare 1970 | 16 epileptic patients were administered diazepam (5–10 mg 3x/day) and assessed with WPRS (Wittenborn psychiatric rating scale) | Scores for psychotic belligerence were markedly reduced. |
Guldenpfennig 1973 | 45 epileptic patients aged 1–58 years were treated for control of seizures with clonazepam (0.5–1 mg/day) initially, and increased to a maximum of 12 mg/day in adults, 4–6 mg/day in children | 3 patients discontinued treatment due to induction of aggression and temper tantrums. |
Kocur et al. 1984 | Case report of aggressive behavior in 35 boys with behavioral disturbances of neurotic or encephalopathic origin | Bromazepam only slightly reduced aggressive behavior in some cases; no change in 6 patients, and increased aggression in 4 cases. |
Rosenbaum et al. 1984 | Case reports of patients treated with alprazolam (0.5–8 mg) for panic disorders, depression, and compulsive disorders | 8 out of 80 patients treated with alprazolam became hostile (physical assault, reckless driving and verbal aggression); only 1 patient had a history of hostile outbursts. |
Strahan et al. 1985 | Case reports of 3 patients with bipolar depression, generalized anxiety, and panic disorders were administered alprazolam (0.25–5 mg t.i.d.); all showed poor impulse control | Alprazolam increased anxiety and panic attacks and produced irritability, agitation, and interpersonal conflicts; symptoms disappeared with discontinuation of alprazolam. |
Pecknold and Fleury 1986 | Case reports of 2 patients with panic disorder and agoraphobia that were treated with alprazolam (4–6 mg/day) | 1–4 weeks of alprazolam treatment induced manic episodes and increased irritability. |
Ward et al. 1986 | Case report of a paranoid schizophrenic | Lorazepam (2–4 mg) reduced agitation and aggressive behavior. |
Keats and Mukherjee 1988 | Case study of a seizure-prone paranoid schizophrenic | Clonazepam (2 mg/kg 4x/day) reduced violent hallucinations and postictal aggressive outbursts. |
References | Methods and Procedures | Results and Conclusions |
Crime |
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Kalina 1964 | 62 patient-inmates were administered diazepam (5–10 mg 2–3x/day for approx. 6 mo.); of the inmates had behavioral problem including violent, destructive, assaultive and aggressive behavior, agitation and active paranoia | Violence (homicidal), destructiveness, assaultiveness, belligerence, and abusiveness were completely controlled in 33 out of 40 inmates with behavioral problems. |
Gleser et al. 1965 | 46 adolescent males in a juvenile detention center were administered placebo or chlordiazepoxide (10 mg/kg 3x day 1 and 20 mg/kg day 2); aggression was assessed during recorded conversations and test period with alarm bell, flashing light, or threat of faradic shock | Anxiety and ambivalent hostility were reduced over time in the chlordiazepoxide group; chlordiazepoxide group showed a trend for reduction in overt hostility. |
Simonds and Kashani, 1979 | Interviews of 109 delinquent boys aged 12–18 years that were committed to a training school to determine relationship between drug abuse and criminal offense. Boys were divided according to crime against property (burglary, auto theft, vandalism or stealing) vs crime against persons (murder, rape, assault or robbery). Drug abuse was determined according to DSM-III criteria | Diazepam was used or abused (1 or more times alone or in combination with other drugs) by 31 person offenders and by 21 property-only offenders, but no significant effects in relation to criminal offense were found for this drug. |
Experimental Studies on Aggression |
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Gardos et al. 1968 | 45 paid college students were grouped according to scores on TMAS (Taylor manifest anxiety scale) as low, medium or high anxiety and administered placebo, oxazepam (45 mg/kg/day in 3 doses) or chlordiazepoxide (30 mg/kg/day in 3 doses) for 1 week; hostility was determined with Buss-Durkee and Gottschalk-Gleser hostility inventories | Oxazepam did not alter hostility in any group, but chlordiazepoxide increased hostile-aggressive tendencies in the medium and highly anxious groups. |
DiMascio et al. 1969 | In a double blind study, 55 normal volunteers received placebo, chlordiazepoxide (15 or 30 mg/kg/day) or exazepam (45 mg/kg/day) for one week; anxiety and hostility were assessed with Scheier and Cattel anxiety battery and Buss-Durkee hostility scale | Chlordiazepoxide increased hostility scores, whereas oxazepam did not. |
Salzman et al. 1969 | 40 male volunteers that had low anxiety and hostility ratings were administered placebo or chlordiazepoxide (10 mg 3x/day for 1–2 weeks). 1/2 of the subjects received instructions that the drug would produce a pleasant, friendly, more relaxed feeling. Subjects were evaluated with Buss-Durkee Hostility inventory | Both the placebo group that received instructions about the drug and the unaware chlordiazepoxide group showed increased hostility ratings. |
Podobnikar 1971 | 36 patients with anxiety related symptoms and neurotic hyperaggressiveness were administered placebo or chlordiazepoxide (10 mg 2x/day) | 11 of 22 patients showed no signs of aggressiveness compared to placebo after 2–4 weeks treatment. |
Salzman et al. 1974 | 48 male volunteers assigned to 3 person groups were evaluated with Buss-Durkee hostility inventory and self-rated and group member-rated questionnaires. Subjects were administered placebo or chlordiazepoxide (30 mg/day) for 7 days | Chlordiazepoxide produced an increase in self-rated hostile affect, but not in behavior hostility. When a frustration stimulus was presented to the group, chlordiazepoxide increased interpersonal behavioral hostility; rage reaction was observed in 1 subject. |
Rickels and Downing 1974 | 225 neurotic outpatients (majority were women) from 3 clinical settings administered placebo or chlordiazepoxide (40 mg/day for 4 weeks); patients were evaluated by physicians and by patient symptom checklist and grouped according to low, medium or high anxiety | All symptoms of hostility, irritability and anxiety were reduced by chlordiazepoxide treatment in all groups. No evidence for increased aggressiveness or "paradoxical rage" reactions. |
Kochansky et al. 1975 | 33 paid volunteers, mean of 24.5 years old, responded to newspaper add that scored greater than 12 but less than 26 on TMAS (Taylor Manifest Anxiety Scale) in discussion groups of 3 were and administered the BDHI (Buss-Durkee Hostility Inventory) before and after group interaction; self administered 15 mg/kg oxazepam, 10 mg/kg chlordiazepoxide, or placebo 3x/day for 1 week tested again 8th day | Following "frustration" stimulus (telling subjects they had performed inadequately and would have to repeat task) chlordiazepoxide increased verbal hostility whereas oxazepam reduced verbal hostility compared to placebo. |
References | Methods and Procedures | Results and Conclusions |
Kochansky et al. 1977 | 32 paid volunteers, 21–29 years old, responding to newspaper ads were classified as medium or highly anxious with TMS (Taylor Manifest Anxiety Scale); discussed TAT (Thematic Apperception Test) cards in groups of 3 in predrug condition; subjects self administered 15 mg/kg oxazepam, 10 mg/kg chlordiazepoxide, or placebo 3x/day for 1 week | ''Frustration" was induced by telling subjects they had performed inadequately and would have to repeat task; chlordiazepoxide reduced total verbal units initially, but following frustration stimulus, increased verbal hostility as measured by viewer-rated aggression scale. Oxazepam reduced verbal hostility even after frustration stimulus. |
Zisook et al. 1978 | 51 outpatients with neurotic anxiety were administered placebo or halazepam (40 mg 2–4x/day) in a double blind study; patients were evaluated with Hamilton Anxiety Scale, MMPI and patient symptom check list | Of the 20 patients that completed the study, halazepam did not alter hostility or anger scores over a 6 week period. |
Lion 1979 | 45 outpatients with histories of temper tantrums, assaultive behavior, and impulsiveness associated with irritability and hostility were administered placebo (4x/day), chlordiazepoxide (25–50 mg 4x/day) or oxazepam (30–60 mg 4x/day); patients were evaluated by physicians and with scored questionnaires using Buss-Durkee Hostility scale and Scheir-Cattell anxiety scale | Oxazepam significantly reduced irritability and hostility measures when compared to placebo or chlordiazepoxide. |
Griffiths et al. 1983 | 12 men with histories of abusing barbiturates and benzodiazepines; 3 subjects also on methadone treatment. Subjects received placebo and two high doses of diazepam (50 and 100 mg/day for 5 days) in a double blind random block design. Subjects filled out questionnaires for drug effect, drug liking, ARCI (Addition Research Center Inventory) and POMS (Profile of Mood States) | Diazepam decreased social interactions and increased ratings of hostility by staff (but not by subject); carry over effects observed in 2 week washout period. |
Gardner and Cowdry 1985 | 16 female outpatients with borderline personality disorder and histories of dyscontrol (suicide attempts, self-abuse, assaults) were administered alprazolam (1–6 mg) or placebo for 6 weeks in a double blind random crossover design | Alprazolam produced episodes of dyscontrol in 7 out of 12 patients (58%) compared to 1 out of 13 patients taking placebo; episodes were more severe, frequent and unpredictable than previous episodes prior to drug treatment. |
Lipman et al. 1986 | 387 outpatients with depressive and anxiety disorders between 18 and 70 years old that answered newspaper add completed a double blind study of 5 medications including chlordiazepoxide (20–60 mg/day for 8 weeks). Subjects completed self-rating check lists, POMS (Profile of Mood State). Physicians evaluated patients progress with HAM-A, HAM-D (Hamilton Anxiety Scale and Depression Scale), anxiety depression check list, Covi Anxiety, and Raskin Depression Screen, and Global Improvement Scale | Patients that received chlordiazepoxide scored consistently higher on measures of anger and hostility than the placebo controls throughout treatment period. |
Literature Reviews |
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Maletzky 1973 | Review of case histories of 22 patients with episodic dyscontrol syndrome evaluated from interviews of patient, family and friends | Relatives and patients noted an increase in violent episodes by chlordiazepoxide and diazepam in 5 patients. |
Salzman et al. 1975 | Review of 28 references of clinical reports and research on oxazepam and aggression | No clinical observation of increased hostility from oxazepam administration. In laboratory, oxazepam reduced aggression or hostile mood even in presence of frustration. Oxazepam differs from chlordiazepoxide or diazepam in reference to increased aggression. |
Greenblatt et al. 1975 | Review of 88 references on clinical pharmacology of flurazepam | In animals, flurazepam produces taming effects in some cases and in other cases produces an increase in aggressive hostile behavior, possibly by releasing anxiety-bound aggression. |
Azcarate 1975 | Review of 43 references on treatment of aggression | Clinical trials of the efficacy of minor tranquilizers have revealed results similar to preclinical animal studies; some studies report increases in hostility and a paradoxical rage reactions; Variations in results may be attributed to dose, specific compound administered, acute vs. chronic administration, individual baseline levels of anxiety and/or hostility, and personality type. |
References | Methods and Procedures | Results and Conclusions |
Zisook and Devaul 1977 | Review of case studies | Chlordiazepoxide and diazepam can produce rage attacks, whereas oxazepam does not; chlordiazepoxide can increase interpersonal hostility and frustration. |
Bond and Lader 1979 | Review of 49 references on benzodiazepines and hostility in normal and violent individuals | Evidence for rage attacks in patients administered benzodiazepines is based on uncontrolled clinical studies and few case histories. Generally, outbursts occur in patients who received doses in excess of 50 mg/day, perhaps due to drug toxicity. Increased hostility by benzodiazepines has been observed in normal subjects in controlled laboratory experiments; chlordiazepoxide increases hostility after 1 week administration, but oxazepam does not produce these results. |
Valzelli 1979 | Review of 129 references on the effects of sedatives and anxiolytics on aggression | Benzodiazepines reported to increase and decrease aggression in man and animals. Suggests drugs that are capable of lowering aggression are equally capable of enhancing it. |
Gunn 1979 | Review of 20 references on the use of drugs in the violence clinic | Increases in hostile aggressive tendencies, and in some cases, aggression and violence, have been observed in some individuals after acute chlordiazepoxide; oxazepam not implicated in paradoxical "rage" response. |
Lion 1981 | Review of 22 references on medical treatment of violent patients | Benzodiazepines have little antiaggressive activity except in paranoid patients where benzodiazepines reduce hypervigilance. BZD often produce a paradoxical "rage" response in alcoholic patients, possibly by disinhibitory action. |
Atkinson 1982 | Review of 18 references on managing violent hospital patients | Concern with increased aggression in some patients administered diazepam and chlordiazepoxide, suggests shorter acting benzodiazepines like oxazepam because of lack of active metabolites. |
Sheard 1983 | Review of 60 references on psychopharmacology of aggression | Violent states associated with personality disorders are controlled with diazepam (0.15 mg/kg/hour, i.v.); chlordiazepoxide or oxazepam (10 mg 3x/day) is especially useful in epileptic patients. Evidence for benzodiazepine-induced paradoxical "rage" reactions may be explained by toxic reactions, or benzodiazepine withdrawal. No reports of paradoxical "rage" with oxazepam. |
Sharon 1984 | Review of 42 references on the use of benzodiazepines in correctional facilities | The concern of paradoxical rage and increased aggression induced by benzodiazepines in the prison populations is unsubstantiated. Very few studies exist to warrant removal of a potentially helpful agent from an anxiogenic setting. Studies that report increases in aggression fail to consider individuals that are already very aggressive prior to benzodiazepine treatment, as well as predisposing conditions (borderline personality disorder). Suggests care in prescribing benzodiazepines in these individuals, but encourages use in individuals with disabling anxiety. |
Sheard 1984 | Review of 59 references on the clinical pharmacology of aggression | Increases in rage and aggressive outbursts are not strongly supported by clinical data. Reductions in hostility and anxiety in double blind studies in delinquent boys, veteran outpatients and anxious out patients. Increases in hostility and paradoxical rage reactions have been associated with chlordiazepoxide but not oxazepam. In addition to antipsychotic medications, benzodiazepines are useful in treating aggressive and combative behavior related to psychosis. |
References | Methods and Procedures | Results and Conclusions |
Tupin 1985 | Review of 36 references on psychopharmacology and aggression in clinical settings | Anxiolytic substances are used to treat anxious, agitated patients, but have been shown to aggravate violence reactions in some patients, and in a few cases produce paradoxical rage reactions. Suggests importance of treating the basis for aggression, namely the underlying psychiatric and/or medical problem, instead of a symptom. Benzodiazepines are useful in treating outbursts associated with borderline personality disorders, but are not as effective in treating serious panic and combativeness associated with psychosis. |
Yudofsky et al. 1987 | Review of 30 references on pharmacologic treatment of aggression | Benzodiazepines' effect on aggressive behavior is inconsistent. Benzodiazepines can produce paradoxical "rage" in some patients; reductions in aggression occur at higher doses that can produce sedation. Benzodiazepines are helpful for acute management of violence, but chronic use not recommended. |
Eichelman 1987 | Review of 136 references on neurochemical and pharmacological aspects of aggressive behavior | Benzodiazepines (chlordiazepoxide, diazepam, oxazepam) are claimed to reduce aggressive behavior in psychotic patients, prisoners with schizophrenic and personality disorders, as well as patients with episodic dyscontrol and hostile outbursts. However, rage reaction and enhanced aggressive behavior have been reported in some patient populations in open clinical trials. Oxazepam less associated with increases in aggression than chlordiazepoxide, but notes need for blind clinical trials. |
Brizer 1988 | Review of 145 references on psychopharmacology and the management of violent patients | Evidence for the efficacy of benzodiazepines for controlling aggression is inconclusive. Although in open clinical trials, chlordiazepoxide, diazepam and oxazepam have been shown to reduce measures of hostility and/or aggression in schizophrenics, epileptics, and patients with organic brain dysfunction and episodic behavioral outbursts, some anecdotal reports indicate an increase of paradoxical rage reaction may be associated with benzodiazepines. Notes the lack of adequate controls for concurrent medications, medication blood levels, and psychiatric and neurologic diagnosis. |
Dietch and Jennings 1988 | Review of case reports and experimental studies | Clinically used BZDs increase irritability, verbal aggression, assaultiveness and self mutilation; incidence of aggression is estimated at 1% of patients treated with BZDs, with differential effects with different BZD compounds. Clonazepam most likely to induce aggression, and oxazepam least likely. |
B. 5-HT1A Receptor Agonists |
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Treatment of Inpatients |
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Ratey et al. 1989 | Case reports in mentally retarded patients | Buspirone (5–15 mg 3x/day) reduced aggression, self-injurious behaviors and maladaptive behavior in 9 out of 14 patients. |
Ratey and O'Driscoll 1989 | Case reports in mentally retarded patients | Buspirone (5–15 mg/kg 3x/day) reduced agitation in 10 patients; however some showed an increase in hyperactivity and agitation at higher doses. |
C. ß-Blockers |
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Treatment of Inpatients |
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Polakoff et al. 1986 | Case study of an extremely violent 36 year old retarded man on mesoridazine (120 mg/d) + propranolol (120–200 mg/d) or nadolol (80 mg/d). | ß-blocker in combination with neuroleptic treatment stopped assaultive behavior and allowed outpatient status after 26 years of institutionalization. |
References | Methods and Procedures | Results and Conclusions |
Luchins and Dojka 1989 | Evaluation of mentally retarded with aggressive and self-injurious behaviors; patients received propranolol (90–410 mg/day) or lithium (600–1800 mg/day) | Aggression and self-abuse were controlled by either propranolol (83% reduction in both behaviors) or lithium (64% reduction for aggression, 82% reduction for self-abuse). |
Elliott 1977 | Case reports of 7 belligerent patients (2 exhibited explosive rage responses) with acute brain damage who received propranolol (60—320 mg/day). | Propranolol reduced irritation and anger, prevented aggressive outbursts and violent rage reaction. When propranolol was discontinued, symptoms reappeared in most cases. |
Schreier 1979 | Case report of 12 year old boy with postencephalitic psychosis administered 20 mg propranolol b.i.d. increased to 100 mg over 2 days with other medications; maintained on propranolol for 2 weeks | Propranolol reduced agitation and verbal aggression over the 2 week treatment period. The day after the last dose, he became increasingly aggressive and destructive (breaking pictures, wrecking room, tearing clothes); propranolol was reintroduced and symptoms disappeared. |
Yudofsky et al. 1981 | Case reports of 4 inpatients with Chronic Brain Syndrome and episodes of aggressive and violent outbursts; propranolol (320–520 mg/day) administered with other medications | Propranolol eliminated rage and violent outbursts and improved social ability with no adverse effects when carefully monitoring vital signs. |
Williams et al. 1982 | Case reports of 26 male and 4 female patients (9 were inpatients) ranging in age from 7 to 35 years with organic brain dysfunction; all had ongoing psychiatric and/or neurological disturbance since childhood or adolescence and prior pharmacological intervention. Patients received 10–20 mg propranolol 3–4x/day initially, and were titrated upwards to achieve a maximal dosage of 50–1600 mg/day | 12 patients showed marked improvement and 12 patients showed moderate improvement in control of rage outbursts following propranolol treatment; side effects included hypertension, somnolence and lethargy. One patient showed bradycardia when taking dose twice (=320 mg). |
Ratey et al. 1983 | Case reports of 3 brain damaged or mentally retarded patients with episodes of provoked and unprovoked rage. Propranolol (90–300 mg/day) was administered with other medications. | All three patients that had been unresponsive to other medications, showed improvement in control of temper tantrums and rage outbursts following propranolol treatment. When propranolol dosage was reduced rage episodes returned. Symptoms subsided with reinstitution of propranolol. One patient showed bradycardia at 300 mg/day. |
Greendyke et al. 1984 | Case reports of 6 assaultive patient with organic brain disease administered propranolol (200–520 mg/day for 40–80 days); assault behavior recorded by shift nurses and observations were conducted 15 minutes every 2 hours 7 times a day | Results indicate a minimum of 1 month administration for effective treatment; propranolol decreased assaultive behaviors, pacing, agitation, and resistiveness. |
Yudofsky et al. 1984 | Case report of 40 year old male alcoholic with Korsakoff's psychosis; extremely violent, physical assaults included injury to nursing staff and self; required physical restraints (ankle and hand or camisole). 20 mg x 4/day increased to 150 mg x 4/day in addition to other medications (haloperidol, phenytonin, pentobarbitol) | Rage attacks were markedly reduced allowing removal of physical restraints; when propranolol dosage was reduced rage attacks returned, but disappeared with reinstitution of propranolol. No adverse effects were observed. |
Ratey et al. 1986 | 19 institutionalized mentally retarded patients given propranolol (40–200 mg/d) along with current medications | 16 of 19 showed less assaultive and self-injurious behaviors when on ß-blocker. Attribute effects to a lowered level of arousal. |
Sorgi et al. 1986 | Retrospective chart review of 7 assaultive chronic schizophrenics given ß-blocker, nadolol (40–160 mg/d) or propranolol (80 mg bid), in addition to their normal antipsychotic medication. | Six of the seven patients improved. Four had > 70% reduction in assaultive behavior. Average peak effect was seen after 12 weeks of ß-blocker. |
Whitman et al. 1987 | Three chronically aggressive psychotic patients treated with doses of propranolol up to 600 mg/d | Treatment with ß-blocker plus neuroleptics resulted in remission and prevented assaultive behavior in one of three patients. Site of action is uncertain. |
Ratey et al. 1987 | 8 autistic adults given propranolol (120–420 mg/d) and/or nadolol (120 mg/d) and behavior evaluated over 2–19 months. | ß-blocker treatment resulted in reduction or cessation of self-abuse and assaultive behavior in all 8 patients. Emphasizes possible soothing effect of ß-blockers. |
Experimental Studies on Aggression |
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Lindem et al. 1990 | 22 mentally retarded patients received pindolol or placebo in a double blind study for 16 wks. Destructive behaviors assessed with the Modified-Overt Aggression Scale. | Frequency of destructive acts decreased by 30% with ß-blocker, the patients' communication (47%) and socialization (149%) also improved markedly. |
References | Methods and Procedures | Results and Conclusions |
Ratey et al. 1990 | Chronic psychiatric patients with histories of aggression received nadolol (n=20) or placebo (n=26) in a double-blind study. | Nadolol (beta-blocker) significantly reduced aggressive outbursts and decreased severity of illness. Effects required 1–2 weeks. |
Literature Reviews |
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Sheard 1984 | Review of 59 references on clinical pharmacology of aggressive behavior | Propranolol (60–320 mg/day) has been used successfully in treating irritability, temper outbursts, and explosive rage responses, particularly in patients with organic brain dysfunction. Notes return of symptoms when propranolol is withdrawn. Improvement does not include primary symptoms of disease (disorientation, memory impairment, or psychotic thinking). Side effects include low blood pressure, headaches, dizziness, fatigue, insomnia, and depression. |
Mattes 1986 | Review of 100 references on the pharmacological treatment of temper outbursts | Propranolol treatment has been successful in controlling temper outbursts in patients with severe organic brain disease, brain-damage, belligerence, Korsakoff's psychosis, schizophrenia, and in violent elderly individuals, yet no predictors of benefit are found. Mechanism of action in controlling outbursts in uncertain; may be related to membrane stabilizing effect, alteration of brain cetacholamines and/or indoles, elevation of seizure thresholds, or action on serotonergic systems. |
Eichelman 1987 | Review of 136 references on neurochemical and pharmacological aspects of aggressive behavior | Propranolol has been reported to effectively reduce aggressive behavior in patients with organic brain injury, Korsakoff's psychosis, schizophrenics, and children with organic impairment in open clinical trials. |
Horn 1987 | Review of 58 references on control of disruptive, aggressive behavior in brain-injured patients | Although FDA (Food and Drug Administration) has only approved the use of ß-blockers for cardiovascular disorders, they have been used with success in patients with anxiety disorders and for control of violent and disruptive behaviors; highlights lack of a specific symptom complex, EEG finding, injury location or temporal relationship to guide clinicians in treating patients as well as difficulty in determining length of treatment and control of side effects. Suggests treatment range starting at 60–129 mg/day divided in 2–3 dosages and gradual increases to a maximum of 800 mg/day. |
Brizer 1988 | Review of 145 references on psychopharmacology and the management of violent patients | Propranolol and other ß-blockers have been successful in controlling aggressive patients with organic brain syndromes, Korsakoff's psychosis, viral encephalitis, schizophrenia, autism, episodic dyscontrol and explosive disorders. Most patients were previously refractory in multiple medication trials, but treatment is particularly effective in patients with organic brain disease. Exact mechanism of action unclear as patients often receive ß-blockers with other medications (e.g. neurleptics). Side effects include hypertension, bradycardia, and depression, but are not frequent with careful monitoring at suggested doses (up to 800 mg/day). |