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The clinical treatment of violent behavior shows a remarkable congruence with preclinical research concerning the modulations of central neuro­ transmitter systems and their influence upon human aggressive behavior. Moreover, systematic alterations of central neurotransmitter activity in patients offer substantial promise of increasing the successful biological modification of violent behavior.

Four groups of rats—controls, blinded, devibrissaed, and bulbectomized—were tested pre- and post-operatively on shock-induced fighting and spontaneous mouse-killing. Jump-flinch thresholds were determined for all animals. Shock-induced fighting decreased significantly for the devibrissaed rats, but did not change for any other group. Bulbectomized animals showed a postoperative increase in mouse-killing. Jump thresholds were lowered for rats with total bulbectomies, but remained stable for all other groups.

A significant increase in shock-induced aggression occurs in the rat 4 days after an intraventricular injection of 90 micrograms of 6-hydroxydopa. Both fluorescent histology and biochemical assay demonstrate that brain norepinephrine is reduced by 90 micrograms of 6-hydroxydopa, while brain dopamine remains unaltered. This suggests that one form of aggressive behavior (shock-induced aggression) is modulated through a central noradrenergic system.

Previous research has demonstrated a fall in systolic blood pressure in the rat measured 2--5 min following shock-induced fighting. This blood pressure fall appears to depend on intact CNS catecholamine neurons. The locus coeruleus is known to supply noradrenergic neuron terminals to much of the brain. In this study, we attempted to identify the location of the CNS catecholamine neurons mediating the blood pressure response to fighting by studying the blood pressure response to shock-induced fighting in locus coeruleus-lesioned and shamlesioned rats. The locus coeruleus-lesioned animals showed a blood pressure increase after fighting on the average across 2 days of testing, while sham-lesioned animals showed a blood pressure decrease after fighting. The difference between the blood pressure responses of the two groups was highly reliable. Since both histofluorescence and biochemical studies indicated that CNS norepinephrine levels were decreased in lesioned as compared to control animals, the findings are interpreted as showing that noradrenergic neurons originating in the locus coeruleus play an important role in mediating aspects of the relationship between fighting behavior and blood pressure response.

A significant decrease in blood pressure is observed after shock-induced fighting in intact rats. In rats treated with intravenous 6-hydroxydopamine, a drug that selectively destroys peripheral sympathetic nerve endings when given by this route, this blood pressure response is reversed to a significant increase. In contrast, adrenalectomy converts a slight increase in blood pressure after intact rats are shocked alone in the cage into a significant decrease. These alterations in blood pressure response suggest that the sympathetic response to a stressful stimulus is not an all or none response, but, rather, consists of a patterned activation depending upon the behavioral response available. The current physiological findings are consistent with neuroendocrine research in which coping behavior is found associated with a predominant norepinephrine release by the sympathetic nervous system, and stress without available coping responses is associated with release also of epinephrine.

A substantial body of research with both animals and humans demonstrates that pharmacologic modulation of three neurotransmitter systems (the GABAergic, the noradrenergic, and the serotonergic) and electrical stimulation of regions of the brain produce marked alterations in aggressive and violent behavior. The author reviews this research and uses case reports to illustrate how it has been applied in the development of a rational pharmacotherapy for violent patients. Four basic principles of clinical application that can enhance trials of pharmacologic treatment of the violent patient are identified. Evidence suggests that behavioral and social learning approaches to the treatment of violence can be more effective when administered after the patient has been stabilized through pharmacologic interventions.

Shock induced fighting, mouse killing, and jump thresholds were measured in gentically hypertensive or hypertensive-prone rat strains and in normotensive and surgically induced (renal) hypertensive rats. Differences in levels of shock induced agression and jump thresholds were observed, but were not a direct effect of hypertension and appeared to be traits genetically separate from the susceptibility to hypertension.

Three to four days following a single intracisternal injection (200 μg) of 6-hydroxydopamine hydrobromide (6-OHDA) there is a marked and persistent increase (400%; p < 0.001) in the number of attacks occurring during shock-induced fighting in male Sprague-Dawley rats 60–70 days old. This attack increase appears to correspond with 6-OHDA's effect of depleting brain dopamine (DA) and norepinephrine (NE) and the degeneration of DA and NE terminals. A subsequent dose of 6-OHDA (200 μg) increases attack rates still further. There is no significant difference in jump thresholds or mouse-killing between 6-OHDA rats and controls.

Administration of 6-hydroxydopamine (6-OHDA) (i.c.) to rats produced a decrease in brain catecholamines (CA) and an increase in footshock-induced fighting. Desmethylimipramine reduced this effect while lessening CA depletion. Blockade of CA synthesis by either α-methylparatyrosine (AMPT) or FLA-63 did not produce any increase in shock induced-fighting. d - or l -amphetamine transiently decreased the 6-OHDA effect. l -DOPA plus MK 486 effectively blocked it. Apomorphine reversed the 6-OHDA effect but was accompanied by pronounced stereotyped behavior. The results suggest that CA depletion alone is not sufficient to produce a facilitation of shock-induced aggression. Degeneration of brain adrenergic terminals produced by 6-OHDA is also requisite for the observed effect. However, the 6-OHDA effect may be transiently altered by drugs which release CA, effect the synthesis of new CA, or, act directly on the CA receptor.

Removal of the olfactory bulbs in male Osborne Mendel rats lowers cortical brain norepinephrine without altering brain dopamine or serotonin levels. No difference in brain amines was found between rats which became mouse-killers following surgery and those which remained non-killers. Both shamoperated controls and bulbectomized rats had elevated levels of the adrenal enzyme tyrosine hydroxylase. The bulbectomy group had heavier adrenals than control groups.

Male Sprague-Dawley rats were subjected to 4 weeks of daily periods of immobilization stress. One of two experimental groups was allowed 1 month of recovery. After 4 weeks of stress, there was a significant increase in shockinduced fighting, in the activity of serum dopamine-beta-hydroxylase, and in the activity of hypothalamic tyrosine hydroxylase. The concentration of hypothalamic norepinephrine was not decreased. After 4 weeks of recovery, only serum dopamine-betahydroxylase activity returned to normal; it therefore appears that longterm stress may increase central catecholamine synthesis. possibly resulting in a persistent increase in aggressive behavior.

A significant fall in tail blood pressure occurs in paired rats after shock-induced aggression. Pressure returns to baseline levels within 4 hours after fighting. Conversely, single rats subjected to jump threshold measurements or to shocks identical to those used in the aggression paradigm show significant elevations in tail blood pressure. The size of the pressure increase in rats shocked alone appears dependent on the intensity of the shocks, while the pressure fall in rats shocked in pairs occurs over a broad range of shock intensities.