The Neurobiological Bases for Development of Pharmacological Treatments of Aggressive Disorders

Allan      Siegel; Suresh      Bhatt; Rekha      Bhatt; Steven   S.   Zalcman

Abstract

Violence and aggression are major causes of death and injury, thus constituting primary public health problems throughout much of the world costing billions of dollars to society. The present review relates our understanding of the neurobiology of aggression and rage to pharmacological treatment strategies that have been utilized and those which may be applied in the future. Knowledge of the neural mechanisms governing aggression and rage is derived from studies in cat and rodents. The primary brain structures involved in the expression of rage behavior include the hypothalamus and midbrain periaqueductal gray. Limbic structures, which include amygdala, hippocampal formation, septal area, prefrontal cortex and anterior cingulate gyrus serve important modulating functions. Excitatory neurotransmitters that potentiate rage behavior include excitatory amino acids, substance P, catecholamines, cholecystokinin, vasopressin, and serotonin that act through 5-HT2 receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT1 receptors. Recent studies have demonstrated that brain cytokines, including IL-1β and IL-2, powerfully modulate rage behavior. IL-1β exerts its actions by acting through 5-HT2 receptors, while IL-2 acts through GABAA or NK1 receptors. Pharmacological treatment strategies utilized for control of violent behavior have met with varying degrees of success. The most common approach has been to apply serotonergic compounds. Others included the application of antipsychotic, GABAergic (anti-epileptic) and dopaminergic drugs. Present and futures studies on the neurobiology of aggression may provide the basis for new and novel treatment strategies for the control of aggression and violence as well as the continuation of existing pharmacological approaches.

Keywords: Aggressive behavior, cytokines, defensive rage, enkephalins, GABA, impulsive behavior, predatory attack, serotonin