Human Aggression: What's Animal Research Got to Do With It?
Neal G. Simon and Emil F. Coccaro
Simon, a three-time HFG grantee, is a professor and chair in the Department of Biological Sciences, Lehigh University. Coccaro, a two-time HFG grantee, is director of the Neuroscience Research Unit at the Hahnemann School of Medicine, Philadelphia, PA.
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Human aggression is clearly an important issue for our society. U.S. rates of homicide and other serious violence are extraordinarily high compared to those of other industrialized nations. In addition, approximately 25% of all adult males, and somewhat less than half this percentage of adult females, report a history of physical fighting at least once since age 18 (Robins and Regier, 1991). Thus, approximately 10-15% (25-40 million) of the general population has engaged in physical fighting, at the least, at some time as an adult. Given that this figure does not include forms of aggression that, though less severe, can nevertheless cause emotional distress and social and vocational impairment, it is evident that aggressive behavior is an important social problem.

Through research over the past two decades, it has become clear that human aggression is not simply "bad behavior" and that problematic impulsive aggression can be viewed as an identifiable behavioral disorder with genetic, biological, and treatment correlates. This research has occurred on two fronts—animal research involving lower- and higher-order nonhuman subjects and clinical research with people—and basic research with animals has often sparked work in human populations. Yet there are significant gaps in communication between these research constituencies, which hinders overall progress in the field. Defining effective strategies that can bridge basic and clinical research approaches in the analysis of aggression was the focus of an HFG workshop in Toledo, Spain, in 1996. The goals were to improve understanding of the research directions within each community, define how to better link basic and clinical experimental perspectives, and understand the opportunities and risks that accompany generalizations across approaches.

Research in Human Aggression: The Critical Relevance of Animal Studies

Modern research into the biology and treatment of human aggression began in the 1960s and 1970s with observations that centrally active biological substances (e.g., neurotransmitters, neuromodulators, and hormones) either inhibited or facilitated aggression in lower animals. For example, destruction of brain serotonin (5-HT) cells and pathways was associated with an increase in aggression in rodents. Conversely, administration of drugs that increased brain 5-HT was associated with a reduction of aggression in these animal models. At the same time that this work was proceeding in animal laboratories, clinical investigators noted that 5-HT levels were reduced in the brains of individuals who committed suicide compared to those who died from equally violent causes but not by their own hand. Subsequent studies in living patients by Marie Asberg and colleagues assessed the levels of 5-HT metabolites (breakdown products) in cerebrospinal fluid, the fluid that bathes the brain. They found that 5-HT metabolites were reduced in concentration in depressed subjects who had attempted suicide by violent means. Clinical investigators turned to the animal literature to understand the association between brain 5-HT and violent suicide. This literature supported the idea that suicidal subjects with low brain 5-HT might be more violent than nondepressed subjects with normal brain 5-HT.

While this apparent similarity between basic and clinical observations was an exciting development, it also was a portent of traps that awaited those who sought to generalize from animals to humans too quickly. In this instance—and this is a theme that will be repeated in this essay—animal models were based, for the most part, on naturally occurring behaviors, that is, behaviors that are typical of members of a population and are adaptive. In the human case, violent suicide can hardly be viewed in this way. Self-directed and obviously maladaptive, it is not an appropriate analog to most animal models. While the finding in both cases of changes in 5-HT function was compelling and suggested a potentially pervasive role for this neurotransmitter across the spectrum of aggressive and violent behaviors, it was clearly possible that underlying brain circuitry and sites of 5-HT action were very different.

Another early example of the cross-fertilization of animal and human research is the work of Michael Sheard. In the 1970s, Sheard had been working with the anti-manic agent lithium carbonate. Based on animal research demonstrating that lithium increased 5-HT, he treated aggressive rodents with lithium to test the hypothesis that increasing 5-HT would reduce aggressive responding. The experiment worked and he next moved to treating prison inmates with lithium. In this four-month study, Sheard gave lithium or placebo (a sugar pill) to approximately 40 prison inmates. The results were remarkable. While lithium had no effect on nonviolent behavior (stealing, lying), it appeared to fully suppress serious assault in inmates as observed and documented by prison guards. Most notable, only impulsive aggressive behavior was affected. Even more important was the observation that impulsive aggression returned to previous levels in the lithium-treated subjects after they were switched to the placebo condition.

Sparked by the work of Asberg, Sheard, and others, Gerald Brown showed that central levels of 5-HT metabolites correlated inversely with life histories of aggression and suicidal behavior in young navy recruits. That is, the lower the concentration of the central 5-HT metabolite, the more aggression reported by subjects and the more likely the subject had a history of a suicide attempt. Later, in the 1980s, Markkuu Linnoila showed that violent offenders (those who had committed or attempted homicide) also had low central levels of 5-HT metabolites, provided that their aggressive behavior had been impulsive in nature.

These and related studies strongly suggested a role for serotonin in a history of impulsive or violent behavior. While this was important clinically, it raised a significant question: where and how in the brain was the serotonin deficiency leading to increased aggression? Advances in basic psychopharmacological research had already pointed to the existence of several subtypes of serotonin receptor, raising the possibility of more specific treatments for impulsive aggression. Here was a case where observations in humans were a strong impetus for drug development. The key goal of research and development was to establish animal models for screening a broad array of potential psychotherapeutic agents. Berend Olivier tested many serotonergic drugs before settling on eltoprazine, a mixed 5-HT1A/1B agonist, as a potential compound for clinical use. While unsuccessful in clinical trials, this compound is nevertheless representative of the effort required for the development of a highly specific drug for the management of inappropriate aggression, one that will reduce such aggression without affecting other behavior.

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