The Neurobiological Bases for Development of Pharmacological Treatments of Aggressive Disorders
Allan Siegel1,2,*, Suresh Bhatt1 , Rekha Bhatt1 and Steven S. Zalcman2
Department of Neurology & Neurosciences, NJ Medical School, UMDNJ, Newark, NJ 07103, USA, 2Department of Psychiatry, NJ Medical School, UMDNJ, Newark, NJ 07103, USA
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 theneural 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. Excitatoryneurotransmitters 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-1 and IL-2, powerfully modulate rage behavior.IL-1 exerts its actions by acting through 5-HT2 receptors, while IL-2 acts through GABAA or NK 1 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.
Key Words: Aggressive behavior, cytokines, defensive rage, enkephalins, GABA, impulsive behavior, predatory attack, serotonin. INTRODUCTION Over the past decade, avariety of studies have been carried out designed to determine the effects of selective drugs on the management of human aggressive behavior. One purpose of the present review is to evaluate human studies with respect to what is known of the neurochemistry and neuropharmacology of aggression. In order to achieve this objective, it is appropriate to first consider the behavioral characteristics andbasic forms of aggressive behavior, the underlying neural substrates, and principal neurochemical and receptor-neurotransmitter mechanisms linked to their expression and control. These features are considered below in the following section. OVERVIEW OF THE NEUROBIOLOGY OF AGGRESSIVE BEHAVIOR Animal Models of Aggressive Behavior In attempting to understand the processes that are collectivelyreferred to as “aggressive behavior”, it is first useful to provide a definition of this term. One encompassing definition is that it constitutes a type of behavior that either threatens harm or leads to or causes harm, destruction or damage to another organism. Such a definition would suggest that aggression is not a unitary phenomenon, but instead, includes a variety of different behavioralprocesses. Such forms of aggression may also reflect competition among organisms of the same or of a different species for mates, food, or territory. Various animal research models of aggressive behavior have been utilized [70,83]. These include: fear-induced, maternal, inter-male, irritable, sex-related, territorial, residentintruder, and predatory aggression. Aside from predatory attack, these models...