Expression Differences During Abstinence Predict Risk Of Alcohol Relapse

戒酒期间的表达差异可预测酒精复发的风险

• 批准号: 8598031
• 负责人: KRISTINE M. WIREN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598031
• 关键词: Abstinence; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Animal Model; Animals; Astrocytes; Behavioral; Bioinformatics; Brain; Brain Injuries; Brain region; Cell Death; Characteristics; Chronic; Chronic Alcoholic Intoxication; Complementary DNA; Consumption; Dependence; Development; Disease; Effectiveness; Effectiveness of Interventions; Ethanol; Female; Gene Expression; Gene Expression Profiling; Genetic; Genetic Models; Genotype; Goals; Heavy Drinking; Impaired cognition; Inbred Strain; Intervention; Intoxication; Lead; Left; Maps; Mediating; Mediator of activation protein; Microarray Analysis; Microglia; Modeling; Molecular Profiling; Mus; Nature; Neurons; Pathway interactions; Phenotype; Prefrontal Cortex; Process; Relapse; Reporting; Resistance; Risk; Seizures; Severities; Signal Pathway; Signal Transduction; Spottings; Structure; Testing; Tissues; Validation; Withdrawal; alcohol abstinence; alcohol exposure; alcohol relapse; alcohol response; alcoholism therapy; base; cDNA Arrays; clinically relevant; density; drinking; effective therapy; in vivo; male; neuroadaptation; neurotoxic; neurotoxicity; new therapeutic target; novel; problem drinker; response; sex; successful intervention; therapeutic target

DESCRIPTION (provided by applicant): Alcoholism is a chronic relapsing disorder associated with excessive consumption after periods of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic intoxication but are poorly characterized in abstinence. We propose that the identification of pathways altered during abstinence in prefrontal cortex, a brain region associated with cognitive dysfunction and damage in alcoholics, will provide information relevant to the risk of relapse in both sexes. To evaluate the influence of genetic differences, animal models with widely divergent responses to alcohol withdrawal are employed, including the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) selected lines. To focus results for phenotype- specific analysis of expression differences, a second model with divergent withdrawal responses, strains of inbred C57BL/6J vs. DBA/2J mice, will also be employed. Male and female mice are chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days. A systematic approach will be taken to characterize significant expression differences important in mediating risk of relapse, with three specific aims. Specific aim 1 will employ high density cDNA transcriptional profiling and bioinformatic analyses to identify novel pathways significantly altered during abstinence that is dependent on withdrawal response phenotype. The second aim will functionally test the ability of identified pathways to influence relapse, using a withdrawal-induced relapse model of elevated relapse drinking for behavioral validation of expression differences. The third aim will define the neurotoxic and neuroadaptive consequences of persistent expression differences in these low and high withdrawal response models, and whether successful reductions in relapse drinking also reduces active neurotoxicity. Our results indicate a fundamentally distinct neuroadaptive response during abstinence in mice genetically selected for divergent withdrawal severity, with increased risk of relapse in animals with a low withdrawal response to alcohol. Identification of pathways altered in abstinence in both sexes will provide clinically relevant toos to aid development of novel therapeutics for targeted treatment of relapse in a subset of abstinent alcoholics.

描述（由申请人提供）： 酗酒是一种慢性复发性疾病，与戒酒后过度饮酒有关。大脑结构、可塑性和基因表达的神经适应在慢性中毒时发生，但在戒酒时却很难表征。我们建议，识别前额叶皮层（与酗酒者认知功能障碍和损害相关的大脑区域）在戒酒期间改变的通路，将提供与两性复发风险相关的信息。为了评估遗传差异的影响，采用了对酒精戒断反应差异很大的动物模型，包括戒断性癫痫发作（WSR）和戒断性癫痫易发（WSP）选定的品系。为了集中表达差异的表型特异性分析的结果，还将采用具有不同戒断反应的第二种模型，即近交系 C57BL/6J 与 DBA/2J 小鼠品系。雄性和雌性小鼠长期暴露于高浓度乙醇中并戒断，然后禁欲 21 天。将采取系统方法来表征在调节复发风险中重要的显着表达差异，并具有三个具体目标。具体目标 1 将采用高密度 cDNA 转录谱和生物信息学分析来识别在戒断期间显着改变的依赖于戒断反应表型的新途径。第二个目标是功能性测试已确定的影响复发的途径的能力，使用戒断诱导的复发饮酒模型来对表达差异进行行为验证。第三个目标将定义这些低和高戒断反应模型中持续表达差异的神经毒性和神经适应性后果，以及成功减少酗酒是否也会减少主动神经毒性。我们的结果表明，对于不同戒断严重程度进行基因选择的小鼠，在戒断期间存在根本不同的神经适应性反应，而对酒精戒断反应较低的动物则复发风险增加。鉴定两性戒酒改变的途径将提供临床相关的工具，以帮助开发新的疗法，用于有针对性地治疗一部分戒酒者的复发。