NEUROBIOLOGICAL MECHANISMS CONTROLLING AGGRESSION - PRECLINICAL DEVELOPMENTS FOR PHARMACOTHERAPEUTIC INTERVENTIONS

Current pharmacotherapeutic approaches to the management of violent an d aggressive behavior rely mostly on agents that act as receptor agoni sts or antagonists at subtypes of brain dopaminergic, GABAergic, and s erotonergic receptors. Ethological experimental studies in animals hav e shown that drugs may modulate aggression by inhibiting motor activit y, by distorting aggression-provoking or -inhibiting signals, by fragm enting behavioral sequences or temporal patterning, or by increasing t he rate and intensity of aggressive acts. Evidence from animal studies points to large changes in selected brain dopamine, serotonin, and GA BA systems during and following aggressive and defensive behavior. How ever, the specificity of drugs that are currently used to control aggr essive behavior through their action as agonists or antagonists at sub types of dopamine, serotonin or GABA receptors continues to be of conc ern. Similar to the effects of widely used traditional neuroleptics th at nonselectively antagonize dopamine receptors, the range of behavior s which is suppressed by either D-1 or D-2 receptor antagonists is per vasive. At present, systemic administration of dopamine receptor antag onists in animal preparations does not target aggression-specific mech anisms. The GABA(A)/Benzodiazepine/Chroride ionophore receptor complex is implicated in the aggression-heightening effects of alcohol and be nzodiazepines. Although early reports focused on the ''taming'' effect s of benzodiazepine anxiolytics, low doses may enhance aggression in b oth animals and humans. Benzodiazepine antagonists block heightened ag gression after low doses of alcohol or benzodiazepines. Agonists at ce rtain 5-HT1 receptor subtypes such as eltoprazine are potently effecti ve in reducing aggressive behavior of males and females of various ani mal species under conditions that promote charging offensive-type aggr ession, without adversely affecting nonaggressive components of the be havioral repertoire. However, recent reports indicate that eltoprazine and related compounds may potentiate anxiety reactions in rodents, an d question the behavioral specificity of these substances. Opioid rece ptor antagonists modulate primarily physiological and behavioral respo nses of defense and submission. Defeated animals show tolerance to opi ate analgesia and withdrawal responses upon challenge with opioid rece ptor antagonists. Defensive and submissive vocalizations are potently blocked by opioid peptides. Substances that target specific receptor s ubtypes at serotonergic, GABAergic and opioidergic synapses are most p romising for the selective modification of aggressive, defensive and s ubmissive behavior patterns.