Neurobiological mechanisms controlling aggression: Preclinical developments for pharmacotherapeutic interventions

Current pharmacotherapeutic approaches to the management of violent and aggressive behavior rely mostly on agents that act as receptor agonists or antagonists at subtypes of brain dopaminergic, GABAergic, and serotonergic receptors. Ethological experimental studies in animals have shown that drugs may modulate aggression by inhibiting motor activity, by distorting aggression-provoking or -inhibiting signals, by fragmenting behavioral sequences or temporal patterning, or by increasing the rate and intensity of aggressive acts. Evidence from animal studies points to large changes in selected brain dopamine, serotonin, and GABA systems during and following aggressive and defensive behavior. However, the specificity of drugs that are currently used to control aggressive behavior through their action as agonists or antagonists at subtypes of dopamine, serotonin or GABA receptors continues to be of concern. Similar to the effects of widely used traditional neuroleptics that nonselectively antagonize dopamine receptors, the range of behaviors which is suppressed by either D₁ or D₂ receptor antagonists is pervasive. At present, systemic administration of dopamine receptor antagonists in animal preparations does not target aggression-specific mechanisms. The GABA_A/Benzodiazepine/Chloride ionophore receptor complex is implicated in the aggression-heightening effects of alcohol and benzodiazepines. Although early reports focused on the "taming" effects of benzodiazepine anxiolytics, low doses may enhance aggression in both animals and humans. Benzodiazepine antagonists block heightened aggression after low doses of alcohol or benzodiazepines. Agonists at certain 5-HT₁ receptor subtypes such as eltoprazine are potently effective in reducing aggressive behavior of males and females of various animal species under conditions that promote charging offensive-type aggression, without adversely affecting nonaggressive components of the behavioral repertoire. However, recent reports indicate that eltoprazine and related compounds may potentiate anxiety reactions in rodents, and question the behavioral specificity of these substances. Opioid receptor antagonists modulate primarily physiological and behavioral responses of defense and submission. Defeated animals show tolerance to opiate analgesia and withdrawal responses upon challenge with opioid receptor antagonists. Defensive and submissive vocalizations are potently blocked by opioid peptides. Substances that target specific receptor subtypes at serotonergic, GABAergic and opioidergic synapses are most promising for the selective modification of aggressive, defensive and submissive behavior patterns.