Proteomic Dissection of Withdrawal-Induced Excessive Drinking

戒断引起的过度饮酒的蛋白质组学解析

• 批准号: 7672576
• 负责人: Christine C Wu
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672576
• 关键词: Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amino Acid Substitution; Amino Acids; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Biochemistry; Brain; Breeding; Chronic; Cluster Analysis; Collaborations; Colorado; Complement; Complex; Databases; Dependence; Development; Dissection; Electron Microscopy; Fractionation; Future; Genes; Genetic; Genotype; Goals; Heavy Drinking; Individual Differences; Isotopes; Knowledge; Label; Letters; Longitudinal Studies; Mass Spectrum Analysis; Membrane; Membrane Proteins; Methodology; Modeling; Molecular; Morphology; Mus; Neurosciences; Phenotype; Post-Translational Protein Processing; Procedures; Proteins; Proteomics; Relapse; Relative (related person); Research Personnel; Rewards; Sampling; Shotguns; Structure; Subcellular Fractions; Technology; Time; Tissues; Transgenic Animals; Transgenic Model; Transgenic Organisms; Universities; Withdrawal; adenylyl cyclase 7; alcohol exposure; behavior test; drinking; drinking behavior; mRNA Differential Displays; neuroadaptation; preference; programs; protein expression; protein profiling; validation studies

DESCRIPTION (provided by applicant): Chronic exposure to alcohol results in neuroadaptive phenomena, including tolerance, sensitization, dependence, withdrawal, loss of control of drinking, and relapse that contribute to the development of excessive alcohol consumption. The goal of the INIA (Integrative Neuroscience Initiative on Alcoholism) Consortium is to identify the molecular, cellular, and behavioral neuroadaptations that occur in the brain reward circuits associated with the extended amygdala and its connections. It is hypothesized that genetic differences and/or neuroadaptations in this circuitry are responsible for the individual differences in vulnerability to the excessive consumption of alcohol. We propose to use quantitative proteomics to dissect the molecular mechanisms contributing to the behavioral phenotype of differential and excessive drinking (both baseline drinking and withdrawal induced drinking) in two animal models: 1) Adenylyl Cyclase 7 (AC7) transgenic animals - changes in the copy number of the AC7 gene produces changes in drinking phenotype using the Withdrawal Induced Drinking (WID) paradigm and 2) High Alcohol Preference (HAP)/Low Alcohol Preference (LAP) animals - animals selectively bred for differences in free-choice alcohol consumption by the 2 Bottle-Choice (2BC) paradigm - the selected genotype (changes in multiple genes) contributes to differential baseline drinking. Our goals are 1) to develop and optimize proteomic methodology for the quantitative analysis of enriched brain fractions, 2) to identify global differences in baseline protein expression between selected lines of the two animal models [AC7 transgenic model (AC7 transgenic versus wildtype) and HAP/LAP selective breeding model (HAP versus LAP)], and 3) to globally compare longitudinal changes in protein expression between animals (AC7 transgenic versus wildtype and HAP versus LAP) at selected time points during WID-2BC to identify proteins that contribute to the differential and excessive drinking behaviors.

描述（由申请人提供）：长期接触酒精会导致神经适应现象，包括耐受、敏感、依赖、戒断、饮酒失控和复发，从而导致过量饮酒。 INIA（酒精中毒综合神经科学倡议）联盟的目标是确定与扩展杏仁核及其连接相关的大脑奖赏回路中发生的分子、细胞和行为神经适应。据推测，该回路中的遗传差异和/或神经适应是造成过度饮酒易感性的个体差异的原因。我们建议使用定量蛋白质组学来剖析两种动物模型中导致差异和过度饮酒（基线饮酒和戒断诱导饮酒）行为表型的分子机制：1）腺苷酸环化酶 7 (AC7) 转基因动物 - 拷贝的变化AC7 基因的数量使用戒断诱导饮酒 (WID) 范式和 2) 高酒精偏好 (HAP)/低酒精偏好产生饮酒表型的变化(LAP) 动物 - 通过 2 Bottle-Choice (2BC) 范式针对自由选择酒精消耗差异进行选择性培育的动物 - 选定的基因型（多个基因的变化）有助于差异基线饮酒。我们的目标是 1) 开发和优化蛋白质组学方法 对丰富的大脑部分进行定量分析，2) 识别基线的整体差异 两种动物模型[AC7转基因模型（AC7 转基因与野生型）和HAP/LAP选择性育种模型（HAP与LAP）]，以及3）在WID-2BC期间的选定时间点全面比较动物之间蛋白质表达的纵向变化（AC7转基因与野生型以及HAP与LAP）识别导致差异和过度饮酒行为的蛋白质。