The neurobiological bases for development of pharmacological treatments of aggressive disorders

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-HT(2) receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT(1) receptors. Recent studies have demonstrated that brain cytokines, including IL-1beta and IL-2, powerfully modulate rage behavior. IL-1-beta exerts its actions by acting through 5-HT(2) 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.

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

Fig. (1)

(A) Summary of principal hypothalamic pathways mediating defensive rage behavior to the midbrain periaqueductal gray (PAG). The primary output of the medial hypothalamus to PAG arises from the anterior medial hypothalamus (AH) and receives significant input from the ventromedial nucleus of hypothalamus (VMH). (Modified from Fuchs et al. [30] with permission. (B) Diagrams indicating the principal efferent projections of the PAG associated with defensive rage (affective defense) on left side and quiet biting (predatory) attack behavior on right side. Ascending fibers associated with defensive rage are distributed to the medial preoptico-hypothalamus and caudally to the locus ceruleus, tegmental fields, and trigeminal complex. In contrast, the pathway from the PAG associated with predatory attack includes a more limited projection to the posterior lateral hypothalamus, while the caudally directed fibers are directed to the median raphe and central tegmental fields. (From Siegel and Pott, [85] with permission). (C) Diagram illustrates principal ascending and descending projections of the perifornical hypothalamus associated with predatory attack. Note projections to the PAG, tegmental fields, locus ceruleus, and motor nucleus of trigeminal nerve. (From Siegel and Pott [85], with permission).

Fig. (2)

Anatomical and functional bases by which the amygdala modulates defensive rage and predatory attack. The medial amygdala (ME) projects to the medial hypothalamus (MH). Contained within MH includes two classes of neurons – those containing glutamate (GLUT) and those containing GABA. Both classes of neurons receive excitatory input from ME whose functions are mediated by substance P acting through NK1 receptors. GLUT neurons project to the PAG and are excitatory to neurons in this region, the effects of which are mediated through NMDA receptors (see Fig. 3). Thus, the underlying basis for the powerful excitatory effects of ME upon defensive rage includes a disynaptic pathway whose initial synapse is situated in ME and the second synapse in the PAG. In contrast, the same groups of neurons in ME, which potentiate defensive rage, suppress predatory attack. This phenomenon is manifest through activation of GABA neurons in MH, which then project to the lateral hypothalamus (LH) and thus inhibit those neurons are associated with the expression of predatory attack.

Fig. (3)

Schematic diagram depicting some of the critical neural mechanisms regulating aggression and contained within limbic structures such as amygdala, hippocampus, and prefrontal cortex are activated by sensory signals that reach them through inputs from sensory regions of cerebral cortex and these limbic neurons are further modulated by monoaminergic neurons situated within the reticular formation of the brainstem. Subsequent changes in levels of excitability within the limbic system alter mediated through efferent pathways of limbic structures such as the fornix and stria terminalis to the hypothalamus, causing changes in excitability levels of hypothalamic neurons, thus directly affecting the neural mechanisms control aggression and rage behavior. The expression of predatory attack is generated in the lateral hypothalamus and the descending pathways which engage both autonomic and somatomotor neurons of the lower brainstem. Likewise, the expression of defensive rage behavior is mediated through neurons in the medial hypothalamus and a glutamatergic descending pathway to the midbrain PAG, which in turn, provides feedback through an ascending neuron onto the medial hypothalamus. The medial and lateral hypothalamus mutually inhibits each other through reciprocal GABAergic neurons. Also depicted in this diagram is that 5-HT_1A receptors facilitate and 5-HT₂ receptors suppress defensive rage in both MH and PAG, while NK₁ receptors in both regions facilitate this form of aggressive behavior.

Fig. (4)

Schematic diagram depicts specificity of cytokine modulation of defensive rage behavior. Shown in this diagram are the reciprocal excitatory relationship between the medial hypothalamus (MH) and periaqueductal gray (PAG) in the expression of defensive rage behavior. The reciprocal inhibitory connections between the MH and lateral hypothalamus (LH) are presented in this diagram in order to illustrate the relationships of the defensive rage pathways to those associated with predatory attack. Powerful facilitation of defensive rage from MH is mediated through IL-1 type I and 5-HT₂ receptor mechanisms. A similar mechanism exists in the PAG as well. Suppression of defensive rage within MH is mediated through IL-2 and GABA_A receptor mechanisms. However, IL-2 in the PAG potentiates defensive rage behavior and this potentiating phenomenon is mediated through IL-2 and substance P – NK₁ mechanisms. (Modified from Zalcman and Siegel [103]).