THE HFG REVIEW OF RESEARCH (Vol. 3, No. 1, Spring 1999)
THE BIOLOGY OF AGGRESSION

Human Aggression: What's Animal Research Got to Do With It?
Neal G. Simon and Emil F. Coccaro

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.

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.

At the same time, the steroid literature provides a powerful example of the limitations on generalizing from animals to humans. In non-human species, testosterone plays a critical role in conspecific, intermale aggression. This behavior is adaptive: it provides resource access and reproductive opportunity. Violence in humans does not parallel this behavior. Clinical investigators must look carefully for types of human aggression that are truly analogous. The broad-brush notion of testosterone serving as a general driver for a host of violent behaviors will, in all likelihood, serve only to limit progress in delineating how steroids contribute to human aggression and violence.

A more recent example of how animal studies have directly informed human research involves the continuing studies of impulsively aggressive patients by Emil Coccaro. Coccaro has collaborated in this work with a variety of clinical and basic science investigators. One of these is Craig Ferris, who studies aggression in the golden hamster. He and his colleagues have found that brain vasopressin facilitates aggression in this species. An interesting trivariate relationship among vasopressin, serotonin, and aggression has been found. In an important series of experiments, golden hamsters treated with 5-HT-enhancing agents showed increases in 5-HT, decreases in vasopressin, and decreased aggression. Recently, Ferris measured the amount of vasopressin present in the cerebrospinal fluid of Coccaro's human subjects. He found i) a positive correlation between vasopressin and aggression, ii) an inverse correlation between 5-HT responsiveness and aggression, and iii) an inverse correlation between vasopressin and 5-HT responsiveness. Vasopressin had a significant relationship with aggression even after taking into account the vasopressin-5-HT relationship. Not only is this a good example of how animal data informs human work, it is also an excellent example of an interaction between two different neurochemical systems in the modulation of aggression in human subjects. This work provides a rationale for testing the hypothesis that a vasopressin receptor antagonist will have antiaggressive effects in humans.


The Emerging Frontier

Basic research studies have provided the impetus for clinical investigations that advanced our understanding of the neurobiology of human aggression. For the most part, the animal experiments described here were investigations in behavioral pharmacology. That is, they involved administration of drugs that alter the function of a particular neurochemical, peptide, or hormonal system combined with careful behavioral analyses. There is little doubt that important insights into human aggression and violence have resulted from the concepts developed in this body of work (see reviews by Miczek, et al., 1994 and Olivier, et al., 1994). An important question is where the next breakthroughs will occur if the historic pattern of basic research with animals informing human aggression continues. This is an exciting topic because research in animal models of aggression now draws increasingly on technologies that allow us to understand events at the cellular and molecular level. This is part of an important transition in behavioral neuroscience with profound implications for the way regulatory systems will be understood. For example, molecular genetic methods have made possible the differentiation of fourteen different serotonin receptor subtypes.

A key element in this transition has been recognition of the conservation of genes across mammalian and, in some cases, non-mammalian species. This tells us that discoveries at the cellular and gene level in rodents, nonhuman primates, and even worms may be applicable to humans (Hen, 1996; Nelson, 1997, C. elegans consortium, 1998). Thus, the role of particular enzymes, receptors, and genetic polymorphisms (sets of variant forms of a gene) in humans can be systematically evaluated in animal models through such manipulations as gene "knockouts" and site-directed mutagenesis. Recent examples of this approach directly relevant to aggressive and violent behavior include the identification of important roles for tryptophan hydroxylase (TPH), monoamine oxidase (MAO), and nitric oxide synthase (nNOS), all of which are enzymes that affect neurotransmitter synthesis or metabolism as well as certain serotonin receptors.

So what's on the horizon? Among the most intriguing possibilities are those associated with the information explosion in receptor biology, enzymology, and recent insights into the interactions among hormonal, peptide, and neurotransmitter systems, particularly serotonin. As noted earlier, molecular biological methods have identified fourteen different serotonin receptor subtypes. While pharmacologic studies had suggested that multiple 5-HT receptor forms were present in the brain, gene sequencing provided definitive proof. In combination, these studies have established primary roles for 5-HT1A and 5-HT1B receptors in rodent aggression (the human analog of rodent 1B is 5-HT1B). Additional intriguing findings surround nNOS, where knockout mice (lacking the gene for this enzyme) are extremely aggressive, and TPH, an enzyme involved in serotonin production, variants of which have recently been associated with variability in aggression in humans. While there are some limitations to the knockout studies because of developmental considerations (these animals are often abnormal in additional ways because of the missing gene), this technology has provided a powerful tool for characterizing cellular paths involved in the production of aggression. Obviously, these findings provide the basis for developing tailored, highly specific pharmacotherapies for the management of inappropriate, impulsive aggression such as that seen in Intermittent Explosive Disorder (Coccaro et al., 1998).

But is this sufficient? The answer is no, based on recent descriptions of complex interactions between hormonal and neurochemical regulatory systems. Neal Simon has identified specific hormonal pathways that facilitate aggression and has defined how these systems interact with serotonin function. He has demonstrated that the intracellular metabolism of testosterone to estrogen and dihydrotestosterone provides multiple hormonal paths to aggression. These events are not detectable systemically (outside of the cell) and are thus one of the reasons that a clear relationship between blood levels of testosterone and aggressive behavior has been difficult to establish. In turn, it has been found that estrogen and dihydrotestosterone each have different effects on each of the serotonin receptor subtypes, 5-HT1A and 5-HT1B (Simon et al. 1998). Extrapolating from these observations in mice, it is now possible to suggest that treatment strategies, at least for males, will need to take into account the active hormonal system.

The description of interactions among various brain signals represents only an initial step. One workshop goal was to consider new bridging approaches for research. Molecular biology may provide the key. The investigators who participated in the HFG workshop are among those who have helped advance the field through methodologies that span sophisticated neuroanatomical, pharmacological, biochemical, and other cytological methods. Yet this body of work is limited in its implications because it is correlational. In fact, it will be essential to explore the molecular bases for these interactions, raising the need for broadened training if we are to see truly substantive progress. These considerations, discussed in the workshop setting, pointed to the need for the development of multi-disciplinary groups to assess the neurobiology of aggression. This was recognized as an important feature of contemporary science and an approach the Guggenheim Foundation was in a unique position to foster.


Conclusion

There is a significant opportunity for investigators seeking to elucidate the neurobiology of animal and human aggression, one that requires integration and effective communication. Building bridges between basic and clinical scientists is a powerful means for advancing potential treatment strategies. Psychopharmacological and molecular biological tools now allow us to define cellular machinery and, in the near future, imaging technologies may well allow us to see cellular events in real time. The key issue is not one of scientific talent or resources, it is overcoming the parallelism that has accompanied the demands of highly specialized contemporary science. It is incumbent on investigators working on neural and chemical mechanisms underlying aggression to promote cross-fertilization of ideas with clinical scientists. Regardless of orientation, investigators stand to benefit enormously from these exchanges, with emerging concepts improving opportunities for the development of effective intervention strategies.

This article is based on a H. F. Guggenheim workshop meeting, "Insight through Understanding: Bridging Basic and Clinical Neuroscience Approaches to Aggression," held in Toledo, Spain, in January, 1996. The authors were the conference organizers.

Neal Simon, a three-time HFG grantee, is a professor and chair in the Department of Biological Sciences, Lehigh University. Emil F. Coccaro is director of the Neuroscience Research Unit at the Hahnemann School of Medicine, Philadelphia, PA. He has received two HFG research grants.

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