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.

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