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

描述（由申请人提供）：酗酒是一种普遍存在的疾病，具有很强的遗传成分。表征乙醇的行为遗传效应将增加对酒精中毒的理解和改善治疗。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。本应用程序的目的是表征与乙醇戒断和神经肽Y （NPY）和促肾上腺皮质激素释放因子（CRF）肽在中央（CeA），内侧（MeA）和基底外侧杏仁核（BLA）表达的遗传小鼠模型相关的焦虑。中心假设是，与低戒断性惊厥严重程度饲养的小鼠相比，选择性饲养的严重酒精戒断性惊厥小鼠会增加乙醇戒断性焦虑，这与NPY降低和CeA中CRF肽水平升高有关。本提案的具体目的是：(1)在现有的戒断癫痫易发（WSP）和戒断癫痫抵抗（WSR）小鼠的重复系中，使用几种行为分析来测量对比和互补的焦虑相关行为，测量乙醇戒断诱导的焦虑；(2)测量

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.