CSF, blood, or urine (see Table 2, section C). In military personnel rated as highly aggressive in terms of nine categories of lifestyle, the MHPG level in CSF was positively correlated with average "aggression score" (Brown et al., 1979). However, NE turnover rates in the CSF of men convicted of violent crimes did not differ among those that were judged to be premeditated versus those considered to be impulsive (Linnoila et al., 1983). Similarly, DA levels and turnover in CSF of five XYY patients arrested for assaults did not differ from controls (Bioulac et al., 1980).

Several studies attempted to identify indices of catecholamine activity in blood or urine that may characterize aggressive or violent individuals. For example in one series of studies, higher urinary NE values, particularly in response to an upcoming experimental stressful event, appear to be more prevalent in violent incarcerated male patients in a maximum security hospital setting (Woodman et al., 1977; Woodman and Hinton, 1978a, b; Woodman, 1979) than in nonviolent controls. Violent male offenders also differ in their levels of free and conjugated plasma phenylacetic acid, although one study finds increases and another, decreases (Sandler et al., 1978; Boulton et al., 1983).

These correlative studies of indices of catecholamine activity in CSF, blood, or urine provide little support for brain NE as a specific "marker" for aggressive or violent behavior. A promising diagnostic strategy is to examine an individual's catecholamine response to an environmental or pharmacologic challenge rather than to rely on basal levels undergoing circadian rhythmic oscillations. NE, DA, and their metabolites are highly compartmentalized in the brain, and their concentrations are relatively low compared to those in other organs of the body. Conclusions about brain catecholamines and the propensity to aggressive and violent behavior on the basis of peripheral measures are to be considered very tenuous.

The pharmacologic evidence from animal and human studies suggests a permissive role for catecholamines in aggressive and violent behavior. One type of experimental strategy is to compromise catecholamine synthesis, storage, or release; these manipulations reliably reduce aggressive and defensive behavior in animals ranging from mice to monkeys (e.g., Eichelman, 1981; Torda, 1976). Of course, brain catecholamine (CA) systems are of critical significance in a large variety of basic physiologic and behavioral

processes such as sleep/wakefulness rhythmicity, homeostatic and motor functions, and a range of active and reactive behavior patterns. The critical issue in these data is the relative lack of specificity with which these pharmacologic interventions reduce aggressive behavior. Pharmacologic inhibition of catecholamine synthesis, presynaptic storage, or release profoundly alters all active behavior, including aggressive acts. Consistent evidence during the past three decades repeatedly demonstrates that inhibition of the synthetic enzymes tyrosine hydroxylase or dopamine ß-oxidase, as well as depletion of storage sites, decrease many behavioral initiatives, including attacks and threats in mice, rats, cats, and monkeys (see Table 2, section D; e.g., Redmond et al., 1971a,b; Torda, 1976; Katz and Thomas, 1976; Diringer et al., 1982). This evidence emphasizes the necessity of intact catecholamine synthesis, storage, and release for aggressive behavior to occur, but does not establish a specific role for catecholamines in these types of behavior patterns.

A further approach in assessing the role of brain catecholamines in animal aggression is to produce degenerations of catecholamine-containing neurons or, more specifically, those neurons that contain either dopamine or norepinephrine with selective cytotoxic agents and subsequently to measure alterations in aggressive behavior patterns. Rage-like reactions and heightened irritability may be produced by CA-depleting doses of the cytotoxic agent 6-hydroxydopamine (6-OHDA) in laboratory rats, and the indiscriminate biting and defensive reactions can further be amplified by exposure to pain stimuli (e.g., Eichelman et al., 1972; Eichelman and Thoa, 1973; Nakamura and Thoenen, 1972; Geyer and Segal, 1974; Pucilowski and Valzelli, 1986; Beleslin et al., 1986; see Table 2, section D). In contrast to these observations are the suppressive effects of 6-OHDA on aggressive behavior in monkeys when confronting conspecifics (Redmond et al., 1973) or in cats preying on rats (Dubinsky et al., 1973). Of course, destruction of brain catecholamine-containing neurons renders an organism severely impaired in a wide range of important bodily functions, which in turn may be indirectly leading to a hyperreactive defensive mode of behavior.

Another strategy consists of modulating aggressive behavior by the administration of catecholamine precursors. During the 1960s and 1970s the "l-dopa-rage" phenomenon attracted attention, and it continues to serve as evidence for an important role of brain dopamine in aggressive behavior (e.g., Eichelman, 1981, 1987). In laboratory rats and mice, administration of very large doses of

the CA precursor, l-dopa (l-dehydroxyphenylalanine) facilitates or induces indiscriminate biting and other defensive reactions. These reactions are further intensified if the animals are exposed to chronic cannabis, are withdrawn from opiates, have sustained CA neurotoxicity or depletion, or have inhibition of CA synthesis or of monoamine oxidase (see Table 2, section D; Everett, 1961; Vander Wende and Spoerlein, 1962; Randrup and Munkvad, 1966, 1969a,b; Ernst, 1967; Lammers and van Rossum, 1968; Zetler and Otten, 1969; Yen et al., 1970; Lal and Puri, 1971; Benkert et al., 1973; Rolinski, 1973). The relevance of the experimental l-dopa-rage phenomenon to aggressive behavior in animals or human violence is, however, tenuous because it occurs only after massive pharmacologic interventions and consists of behavioral fragments of uncertain significance (e.g., Krsiak, 1974b). L-Dopa actually suppresses fighting behavior in mice but increases defensive responses to painful stimuli (e.g., Karczmar and Scudder, 1969; Thoa et al., 1972a). The amino acid precursors l-tyrosine and l-phenylalanine, if added to the diet, may transiently increase aggressive behavior in mice (Thurmond et al., 1979, 1980). DA, when given directly into the cerebral ventricles, may also increase pain-induced defensive responses in rats (Geyer and Segal, 1974).

Most of the evidence on brain NE and DA derives from studies with increasingly selectively acting receptor agonists and antagonists. Initial evidence indicated that the nonselective DA receptor agonist, apomorphine, results in hyperdefensive responses similar to those seen after l-dopa in mice and rats, particularly under conditions in which brain dopamine receptors are unusually sensitive (see Table 2, section D; e.g., Senault, 1968; McKenzie, 1971; Thoa et al., 1972a,b; Lal and Puri, 1971; Torda, 1976; Baggio and Ferrari, 1980; Pucilowski et al., 1986, 1987). By contrast, in situations requiring coordinated pursuit, threat, and attack, apomorphine exerts suppressive effects on aggressive behavior in mice (e.g., Hodge and Butcher, 1975; Lassen, 1978; Baggio and Ferrari, 1980). These studies suggested a clear pharmacologic differentiation between offensive aggression and exaggerated defense. Recently developed selective agonists for the D1 and D2 receptor subtypes mimic the effects of apomorphine in terms of hyperdefensive and indiscriminate biting reactions in laboratory rodents (e.g., Puglisi-Allegra and Cabib, 1988, 1990; Cabib and Puglisi-Allegra, 1989). A large number of studies have consistently documented the inhibitory effects of catecholaminergic and particularly dopaminergic receptor agonists on killing behavior by omnivorous rats and carnivores (see Table 2, section D; e.g., Schmidt, 1979, 1983; Bandler,