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）：