By the mid-1980s, Emil Coccaro and his colleagues began to look at serotonin in a new way. Small doses of 5-HT-stimulating drugs were given to see how serotonergic brain cells actually respond. In a series of studies in mood- and personality-disordered subjects, Coccaro found that the physiologic (i.e., blood hormone) response to 5-HT stimulation was lower in impulsive aggressive subjects. Moreover, this blunted response was dimensional in nature. That is, the lower the physiologic response to 5-HT stimulation, the greater the history of aggression the subject reported. Subjects with low central 5-HT responsiveness were generally irritable and had a low threshold for acting aggressively. Referral to the animal literature revealed that low 5-HT animals are, in the absence of any stimulation, hyperirritable, a striking commonality.

At the same time, Dee Higley and colleagues were conducting studies on nonhuman primates. Given that these animals share nearly the same genome as humans, these studies were valuable because a number of observations are possible in these species that are not easily available in humans. Higley first replicated the finding of an inverse relationship between central 5-HT metabolites and aggression and impulsivity. Next, the question of a relationship between rearing environment and central 5-HT was explored. These studies found that adverse rearing environments (i.e., motherless rearing) have a deleterious effect on central 5-HT function and aggression. While the environments used in these studies were clearly extreme from a human perspective, these observations suggested that environmental factors play a critical role in the development of the central 5-HT system and aggression.

These investigations provided a stronger bridge between basic and clinical biological research on aggression. The deleterious effects of environmental deprivation on aggressiveness and social function in general had been extensively documented in non-human primates (see Kraemer, 1996 for a review), and changes in 5-HT function now seemed to be an integral part of behavioral alterations. Parallels to human behavior were made stronger by findings drawn from primates. In terms of research direction, then, a useful integrative path can be defined. Rodent models provide the most readily manipulated system. Findings from these investigations can be tested, to the extent possible, in non-human primates. If validated, the assumption of continuity between animal aggression and human aggressive behavior is strengthened.

Serotonin is not the only brain chemical of import in human aggression. Because it functions primarily as a behavioral inhibitor or break against impulsivity, other brain chemicals must be involved in behavioral activation. Here again animal research has led the way. Long before we knew that the neurotransmitter norepinephrine (NE) might play a role in human aggression, animal studies had generated data indicating that it facilitates aggression. As a consequence, treatments with agents that increase NE function (e.g., pre-Prozac antidepressants) have been shown to increase aggression in impulsive aggressive individuals (Soloff et al., 1986). Because the NE system is involved in flight or fight, it is easy to see how increased function of this neurotransmitter could predispose a person to impulsive aggressive behavior. In sum, this biological work indicates that clinically effective antiaggressive agents should enhance 5-HT and dampen (or at least have little effect on) NE function. This is, in fact, the pharmacological profile of most of the currently known antiaggressive agents available for use in humans (e.g., lithium: Sheard et al., 1976; fluoxetine: Coccaro and Kavoussi, 1997).

Other kinds of chemicals, in addition to neurotransmitters, appear to play a role in aggression. Steroid hormones, such as testosterone, have long been known to influence aggressive behavior. The best work in this area has been done in animal models, where a clear relationship between the presence of testosterone and the facilitation of certain forms of aggression has been established. In particular, aggression related to achieving dominance status in nonhuman males has been linked to testosterone, but a systematic relationship between blood levels of this hormone and the amount or intensity of aggression has not been demonstrated.

In humans, a number of investigators have tried to determine how testosterone contributes to aggression (see Archer, 1991). These studies have produced mixed results, which should not be surprising. A number of factors have contributed to the equivocal findings, including methodological issues, the selection of forms of aggression that do not involve testosterone, a perhaps unrealistic perspective among clinical investigators that a graded response exists between blood levels of testosterone and the intensity of aggression, and, as discussed below, the inability (for obvious reasons) in clinical studies to assess events at the cellular level that animal studies have shown are critical to the facilitative effect of testosterone. Despite these problems, there are investigations indicating a correlation between testosterone and some aspects of human aggression. Most recently, positive relationships between testosterone and social dominance were found in adolescent males, and elderly men with higher testosterone were more aggressive than those with lower hormone levels (Finkelstein et al., 1997; Orengo et al., 1996). Also, Virkkunen and coworkers (1996) found higher levels of testosterone in violent offenders. When these findings are considered with reports of "roid rage" and personality changes associated with androgenic anabolic steroid abuse, it is easy to understand the continuing clinical interest in the relationship among testosterone, aggression, and violent behavior.

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