Genetic Mouse Models of Ethanol Withdrawal: Role of CRF and NPY in Anxiety

Oregon Health & Science University, Portland OR

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Alcoholism is a prevalent disorder with a strong genetic component. Characterization of the behavioral genetic effects of ethanol will increase understanding and improve treatment for alcoholism. Alcoholism is associated with physical (e.g., convulsions) and psychological withdrawal symptoms (e.g., anxiety). The psychological symptoms are highly correlated with relapse in alcoholics. The goal of this application is to characterize anxiety related to genetic mouse models of ethanol withdrawal and neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) peptide expression in the central (CeA), medial (MeA) and basolateral amygdala (BLA). The central hypothesis is that mice selectively bred for severe ethanol withdrawal convulsions will have increased ethanol withdrawal-induced anxiety associated with decreased NPY and increased CRF peptide levels in the CeA compared to mice bred for low withdrawal convulsion severity. The specific aims of this proposal are to (1) measure ethanol withdrawal-induced anxiety in the existing replicate lines of Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice using several behavioral assays that measure contrasting and complementary anxiety-related behaviors, (2) measure [unreadable] NPY and CRF peptide expression in the CeA, MeA and BLA using immunohistochemical techniques to before ethanol exposure, immediately following chronic ethanol exposure and at peak withdrawal in chronic ethanol withdrawing WSP and WSR lines. Because WSP lines exhibit more basal as well as more ethanol withdrawal-induced anxiety behaviors than WSR lines, we predict that a genetic relationship between ethanol withdrawal and anxiety exists and that ethanol-withdrawal induced anxiety will be more severe in WSP versus WSR lines in additional models of ethanol withdrawal-induced behaviors related to anxiety. WSP lines are also predicted to have decreased NPY and increased CRF peptide basal levels in the CeA that are associated with anxiety and these effects will be potentiated during ethanol withdrawal. These studies will help elucidate the genetic basis of withdrawal and explore the potential roles of CRF and NPY in anxiety related to alcohol dependence that may lead to promising targets for drug treatments for alcoholism. [unreadable] [unreadable] [unreadable]