Modulation of Effects of Repeated Ethanol Administratio*

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DESCRIPTION (provided by applicant): Our goals are to identify alterations in neurochemistry that occur in the extended amygdala following chronic alcohol administration and examine the hypothesis that endogenous K-opioid receptor (KOR) systems attenuate the neurochemical and behavioral effects of alcohol. We postulate that activation of KOR systems by alcohol is a key homeostatic mechanism that opposes the development of alcohol dependence, and that dysregulation of KOR systems results in altered vulnerability to the reinforcing effects of alcohol and to alcohol addiction. We will test these postulates pharmacologically in wild-type mice, and by using mice with constitutive deletion of the gene encoding the KOR-1 receptor or dynorphin, the endogenous KOR ligand. Specific Aim 1 will characterize alterations in dopamine, GABA and glutamate neurotransmission that occur in the nucleus accumbens (Acb) and central nucleus of the amygdala during abstinence from chronic alcohol administration and determine whether hypofunction of KOR systems exacerbates these effects. The no net flux method of quantitative microdialysis will be used to monitor extracellular dopamine concentrations and changes in dopamine uptake and release. Conventional dialysis will be used to measure basal and stimulus (alcohol, KCI)- evoked dopamine, GABA and glutamate efflux. Specific Aim 2 will determine whether hypofunction of KOR systems alters adaptations in behavior that occur following chronic alcohol administration. We will measure somatic signs of alcohol withdrawal and sensitization of the withdrawal response that occurs after repeated bouts of alcohol intoxication and withdrawal. Specific Aim 3 will determine whether KOR system hypofunction results in increased sensitivity to the rewarding effects of ethanol and whether dopamine dynamics are altered in the Acb and amygdala of mice self-administering alcohol. Operant oral alcohol self- administration will be used to characterize the rewarding effects of alcohol and microdialysis will be used to monitor neurotransmitter dynamics in self-administering mice. The data derived from these studies will delineate neuroadaptations that occur in the extended amygdala following both context-dependent and independent alcohol administration and the role of endogenous opioid systems in modulating the neurochemical effects of alcohol, alcohol dependence, and reward.