The main objective of this proposal is to assess the role of neuropeptide Y (NPY) in the development and maintenance of alcoholism, and to assess whether brain NPY systems represent a viable pharmacotherapeutic target to combat alcoholism. These problems will be examined using a multidisciplinary approach in the context of an animal model of alcoholism that mimics the human condition. This animal model is defined by cycles of chronic exposure to high doses of alcohol, multiple withdrawals from alcohol, and relapse to alcohol drinking, presumably for its ability to alleviate aversive symptoms associated with the absence of alcohol. The proposed experiments will examine the role of NPY at the behavioral, cellular, and molecular levels in the development and maintenance of alcoholism. More specifically, the experiments proposed herein will examine [1] the ability of NPY in the central nucleus of the amygdala to suppress relapse ethanol drinking and withdrawal-related anxiety-like behavior, [2] possible interaction effects of NPY and ethanol on inhibitory neurotransmission in the central nucleus of the amygdala, and [3] changes in levels of NPY receptor subtypes in the extended amygdala during and following the development of alcohol dependence. The overall hypothesis is that NPY systems in the central nucleus of the amygdale are largely dysregulated following induction of alcohol dependence and that these pathological changes are a major factor in driving the dependent organism to relapse, specifically to alleviate the negative affective consequences associated with the absence of alcohol. In accordance with the NIAAA mission, these results will clarify the consequences of alcoholism on the role of brain NPY systems in mediating relapse behavior and may eventually contribute to the development of a novel and effective pharmacotherapeutic agent to combat alcoholism. Dysregulation of brain neuropeptide Y systems is increasingly thought to be a major factor in the maintenance of alcoholism, especially by contributing to the negative affective consequences experienced by alcoholics during the absence of alcohol. Neuropeptide Y has robust anxiety-reducing effects that may be compromised by constant exposure to high doses of alcohol, thus contributing to the motivational factors that lead to relapse alcohol drinking. For the same reasons, brain neuropeptide Y systems represent an excellent candidate for the development of pharmacotherapeutics capable of effectively combating alcoholism in humans.
