The application proposes a career development plan for Dr. Thomas Kash, a post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its neurophysiological basis. The initial, mentored phase of the proposal will be conducted at Vanderbilt University in the laboratory of Dr. Danny Winder. The project focuses on the role of dopamine signaling in the extended amygdala in both acute and chronic aspects of alcohol abuse. The extended amygdala, including the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA) receives substantial dopaminergic innervation, and studies suggest that dopamine signaling in these regions is important in stress and addiction-related behaviors. Interestingly, a major portion of the dopaminergic innervation of this region originates from the A10Dc group of dopamine neurons in the ventral lateral periaqueductal gray (vIPAG), a region strongly implicated in emotional behavior. The present multidisciplinary application uses electrophysiological, anatomical and molecular techniques to determine the mechanisms of dopamine signaling in the BNST and to define the role that A1 Ode dopaminergic neurons play in alcohol abuse. The mentored phase of this award will focus on an in-depth examination of the mechanism of dopamine modulation in the BNST, using genetic and pharmacological approaches to test the hypothesis that acute ethanol alters neuronal function of the BNST through activation of dopamine receptors (Aim 1). The focus of the studies will then shift to focus on the role of the A10dc dopaminergic neurons of the vIPAG in alcohol abuse. The basic characteristics and the ability of ethanol to modulate function of these neurons will be determined using newly available 'reporter' mice (Aim 2). The impact of chronic ethanol exposure on the electrophysiological parameters and biochemical markers of activation in the A10dc dopaminergic neurons, as well as dopamine modulation of function in the BNST will be assessed in Aim 3. Relevance: The project will provide critical insights in to the role of dopamine in the acute actions of alcohol and define the physiologic relevance of an uncharacterized population of dopaminergic neurons in alcohol abuse and dependence. ? ? ?
