The prefrontal cortex exerts a potent regulatory influence over subcortical systems that are involved in the regulation of affective states. In particular, the amygdala is a region that is known to play a prominent role in the expression of emotions, and this function is believed to be disrupted in affec- tive disorders and drug abuse. In addition, dys- function of the prefrontal cortex is believed to be a common element in many psychiatric disorders such as schizophrenia. Using electrophysiological recordings in rodents, we examined the interac- tions of the prefrontal cortex with the amygdala. Our studies showed that these areas are strongly interdependent, with the prefrontal cortex showing conditioned responses that depend on amygdala inputs, and in turn exerting a potent attenuation of activity within the amygdala. In particular, the ability of the prefrontal cortex to modulate amyg- dala activity is likely to play an important role in our ability to cope with stressors. We propose that a dysfunction within the prefrontal cortex disrupts the ability of this region to effectively modulate the amygdala, leaving the organism susceptible to detrimental effects of stressors. This would appear to be a common underlying process that may leave the individual susceptible to drug abuse and to the onset or exacerbation of psychiatric disorders such as schizophrenia and depression. Keywords: Amygdala; Stress; Drug abuse; Schizophrenia; Dopamine; Prefrontal cortex; Affective disorders INTRODUCTION The limbic system is a collection of nuclei involved in the regulation of affect. As such, these regions play a substantial role in disorders which have an emotional or motivational component. This includes such a diverse array of psychiatric disorders as drug abuse, depression, bipolar disorder, and schizophrenia. However, disorders of affect are typically thought to involve disruptions in the higher cognitive centers involved in affective regu- lation. Primary among these is the prefrontal cortex. Our studies show that the prefrontal cortex exerts a powerful inhibitory influence over affective regulation, and moreover that this regulation can be disrupted by overstimulation by the dopamine system or by chronic stress. As such, disturbances at different points in this circuit, and encountered at different developmental stages, can lead to unique but related disturbances that manifest as psychiatric illnesses. STRUCTURE OF THE AMYGDALA: REGULATION OF ACTIVITY BY INTERNEURONS The amygdala is a brain region believed to be responsi- ble for the expression of emotion (LeDoux, 2000). The amygdala complex itself is comprised of a number of subnuclei, which can be divided into two broad catego- ries: the basal/lateral complex which consists of gluta- matergic pyramidal projection neurons, and the central complex, consisting of medium spiny-like GABAergic projection neurons (Kretteck and Price, 1978). The basolateral complex neurons have primarily ascending projections that innervate areas involved in higher cog- nitive processes, such as the evaluation of emotional stimuli and goal-directed behavior (Gray, 1999). In contrast, the central amygdala complex projects pri- marily to areas involved more in autonomic functions related to stress, such as areas that are involved in regulating blood pressure, heart rate, and general stress reactivity (FIG. 1) (Veening et al., 1984). The basolateral complex also has interconnections F.P. Graham Publishing Co. Disruption of Cortical-Limbic Interaction as a Substrate for Comorbidity ANTHONY A. GRACE * Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Grace@ bns.pitt.edu (Submitted 19 October 2005; Revised 18 January 2006; In final form 18 January 2006) *Corresponding author. Tel.: 1 (412) 624-4609; FAX: 1 (412) 624-9198[ E-mail: Grace@bns.pitt.edu ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2006 FP Graham Publishing Co., www.NeurotoxicityResearch.com Neurotoxicity Research, 2006, VOL. 10(2). pp. 93-101