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

乙醇戒断的遗传小鼠模型：CRF 和 NPY 在焦虑中的作用

• 批准号: 7615863
• 负责人: SCOTT Dennis PHILIBIN
• 金额: $ 4.96万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615863
• 关键词: Affective Symptoms; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral; Behavioral Assay; Behavioral Genetics; Breeding; Cell Nucleus; Chronic; Condition; Convulsions; Corticotropin-Releasing Hormone; Dependence; Disease; Drug Delivery Systems; Ethanol; Exhibits; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Goals; Lead; Measures; Medial; Modeling; Mus; Nausea; Neurobiology; Neuropeptides; Peptides; Pharmaceutical Preparations; Preclinical Testing; Range; Relapse; Resistance; Role; Seizures; Severities; Stress; Structure; Symptoms; Techniques; Testing; Withdrawal; Withdrawal Symptom; alcohol abuse therapy; alcohol effect; alcohol exposure; base; biological adaptation to stress; improved; mouse model; neurobiological mechanism; neuropeptide Y; problem drinker; psychologic; response; trait

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.

描述（由申请人提供）：酒精中毒是一种普遍存在的疾病，具有很强的遗传成分。乙醇行为遗传效应的特征将增加对酒精中毒的理解并改善其治疗。酒精中毒与身体有关（例如，惊厥）和心理戒断症状（例如，焦虑）。精神症状与酒瘾复发高度相关。本申请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）中表达的遗传小鼠模型相关的焦虑。中心假设是，与为低戒断性惊厥严重程度而饲养的小鼠相比，选择性饲养的重度乙醇戒断性惊厥小鼠的乙醇戒断诱导焦虑增加，与CeA中NPY降低和CRF肽水平增加相关。该提议的具体目的是（1）使用测量对比和互补的焦虑相关行为的几种行为测定来测量在戒断性癫痫倾向（WSP）和戒断性癫痫抵抗（WSR）小鼠的现有复制系中乙醇戒断诱导的焦虑，（2）测量 采用免疫组织化学技术检测慢性乙醇戒断WSP和WSR细胞系在乙醇暴露前、慢性乙醇暴露后即刻和戒断峰值时CeA、MeA和BLA中NPY和CRF肽的表达。由于WSP系表现出更多的基础，以及更多的乙醇戒断诱导的焦虑行为比WSR系，我们预测，乙醇戒断和焦虑之间存在遗传关系，乙醇戒断诱导的焦虑将更严重的WSP与WSR线在其他模型的乙醇戒断诱导的行为与焦虑。还预测WSP系在CeA中具有与焦虑相关的降低的NPY和增加的CRF肽基础水平，并且这些作用将在乙醇戒断期间增强。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，这可能导致有希望的酒精中毒药物治疗靶点。