This research plan addresses the hypothesis that alcohol-induced activation of the endogenous opioid system serves as a neurobiological mechanism that contributes to alcohol reinforcement and high alcohol drinking. The goal of this proposal is to determine whether opioid peptides function as neural substrates for oral alcohol self- administration and to elucidate the relationship between opioid peptides, dopamine (DA) and GABA in the ventral tegmental area (VTA) and nucleus accumbens (ACB), brain areas that are critically involved in alcohol reinforcement. To achieve these goals the following specific aims will be pursued: l. Determine whether site specific microinfusion of selective opioid receptor antagonists in vivo attenuates oral alcohol self-administration in alcohol-preferring rats of the P and HAD lines under conditions of scheduled-access to alcohol in the home cage and operant responding for oral alcohol reinforcement. 2. Determine whether there are line differences in spontaneous and potassium-stimulated DA and GABA release from the ACB in vitro in rats from the high alcohol drinking lines (P and HAD) compared with their low drinking counterparts (NP and LAD lines) under basal conditions and in response to an alcohol challenge, and identify the opioid receptor subtypes that mediate alcohol-induced DA release from the ACB. 3. Determine whether opioid receptors are involved in regulating the threshold for alcohol aversion in rats selectively bred for high alcohol intake (P and HAD lines). 4. Determine whether opioid peptides mediate the anxiolytic effect of alcohol in rats of the P and HAD lines. The experiments will be conducted using rats selectively bred for alcohol preference and nonpreference which are well suited for the study of genetic differences in neural systems that subserve alcohol reinforcement and alcohol drinking behavior. The results of these studies will provide a better understanding of the role of the opioid system in mediating genetic differences in alcohol drinking behavior.
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