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

描述(申请人提供)：酒精中毒是一种带有强烈遗传成分的流行疾病。对酒精的行为遗传效应进行表征将增加对酒精中毒的理解，并改进治疗方法。酒精中毒与身体(如抽搐)和心理戒断症状(如焦虑)有关。心理症状与酗酒者的复发高度相关。这项应用的目的是表征与酒精戒断遗传小鼠模型相关的焦虑以及神经肽Y(NPY)和促肾上腺皮质激素释放因子(CRF)在中央(CEA)、内侧(MEA)和基底外侧杏仁核(BLA)的表达。中心假设是，与低戒断惊厥程度的小鼠相比，选择性培育成严重戒酒惊厥的小鼠会增加酒精戒断引起的焦虑，并伴随着CEA中NPY的降低和CRF多肽水平的增加。这项建议的具体目的是(1)在现有的戒断发作倾向(WSP)和戒断发作抵抗(WSR)小鼠的复制品系中测量乙醇戒断诱导的焦虑，使用几种衡量对比和互补焦虑相关行为的行为测试，(2)测量 用免疫组织化学技术检测慢性酒精戒断WSP和WSR系在酒精暴露前、暴露后即刻和戒断高峰时CEA、MeA和BLA中NPY和CRF多肽的表达。由于WSP品系比WSR品系表现出更多的基本和更多的酒精戒断诱导的焦虑行为，我们预测在酒精戒断和焦虑之间存在遗传关系，并且在其他与焦虑相关的酒精戒断行为模型中，WSP品系比WSR品系表现出更严重的酒精戒断诱导的焦虑。WSP品系还被预测降低了与焦虑相关的CEA中NPY和CRF肽的基础水平，这些影响将在酒精戒断期间增强。这些研究将有助于阐明戒断的遗传基础，并探索CRF和NPY在与酒精依赖相关的焦虑中的潜在作用，这可能会导致有望成为酒精中毒药物治疗的靶点。

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 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.