Alcoholism is characterized by a cyclic pattern of binging, periods of abstinence, and relapse. Over the time course of the disease, neuroadaptations occur that result in an enhanced state of stress during protracted withdrawal that, in turn, may promote relapse. One such neuroadaptation may be an altered neuropeptide Y (NPY) system. NPY plays a role in the regulation of feeding, anxiety and response to stress, and neuronal excitability. Intracerebroventricular infusions of NPY reduce ethanol drinking in alcohol-preferring P rats, and this effect is markedly enhanced in rats with a history of chronic ethanol consumption punctuated by single or multiple periods of imposed ethanol abstinence. This suggests that NPY system(s) may be altered as a function of ethanol exposure, period(s) of abstinence, or by both. The proposed studies will examine the hypothesis that repeated cycles of chronic drinking, abstinence, and reinstatement will produce neuroadaptive changes in NPY systems that alter (increase) sensitivity to NPY. In doing so, the efficacy and pharmacology of direct and indirect enhancement of NPY activity as a potential clinical strategy will be explored. The duration of chronic ethanol drinking history and the number of periods of imposed abstinence will be systematically varied, and effect of acute NPY administration on ethanol drinking and feeding will be measured in P and Wistar rats (Specific aim 1). The relationship of the effects of NPY on ethanol drinking to feeding, and locomotor activity also will be examined. It is hypothesized that the behavioral effects of NPY will be enhanced as a function of duration of chronic ethanol drinking and/or the number of abstinence periods. The number of consecutive daily NPY infusions will be varied to determine whether tolerance or sensitization occurs to the ability of NPY to reduce ethanol drinking and attenuate relapse (Specific Aim 2). An NPY Y1 receptor antagonist will be co-administered with NPY, and a Y2 receptor antagonist will be administered alone (Specific aim 3). It is predicted that a Y1 antagonist will block the effects of NPY on ethanol drinking. Since Y2 antagonism has the effect of elevating endogenous NPY activity, it is predicted that a Y2 antagonist will reduce ethanol drinking in a manner similar to exogenously administered NPY. The overall hypothesis is that manipulations aimed at increasing NPY activity may be particularly effective treatments when an organism has a history of repeated withdrawal and relapse. [unreadable] [unreadable] [unreadable]