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: 8244753
• 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/8244753
• 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. PUBLIC HEALTH RELEVANCE: One characteristic of alcoholism is uncontrolled excessive consumption of alcohol, characterized by an inability to remain abstinent. Abstinence from alcohol drinking is an important goal for the treatment of alcoholism, but there is limited understanding of factors that influence risk of relapse and as a result few effective treatments. We propose that long-lasting persistent neuroadaptive gene expression changes that occur as a consequence of alcohol abuse and that are dependent on genotype/phenotype are mediators of the risk of relapse during abstinence. Results from these studies will identify novel, previously uncharacterized mechanisms for the development of therapeutics for targeted treatment in recovering alcoholics in both males and females, and may lead to novel targets for sex-specific or targeted treatment or amelioration of brain damage associated with chronic ethanol abuse.

描述（由申请人提供）： 酒精中毒是一种慢性复发障碍，与禁欲后过度消费有关。大脑结构，可塑性和基因表达的神经适应于慢性中毒，但戒酒的特征很差。我们建议，在前额叶皮层禁欲期间改变的途径，与认知功能障碍和酗酒者损害相关的大脑区域将提供与两性复发风险有关的信息。为了评估遗传差异的影响，采用了对戒酒的反应广泛反应的动物模型，包括抗癫痫发作（WSR）和戒断癫痫发作（WSP）选定的线。为了重点进行表达差异的表型特定分析的结果，也将采用第二种具有发散戒断响应的模型，近交C57BL/6J与DBA/2J小鼠的菌株也将被使用。雄性和雌性小鼠长期暴露于高度陶醉的乙醇并撤回，然后戒酒21天。将采用一种系统的方法来表征在介导复发风险的重要表达差异，并具有三个特定的目标。具体目标1将采用高密度的cDNA转录分析和生物信息学分析，以鉴定在禁欲期间显着改变的新途径，这取决于取决于撤回反应表型。第二个目标将在功能上测试鉴定途径影响复发的能力，使用戒断诱导的复发饮酒复发模型来进行表达差异的行为验证。第三个目标将定义这些低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，以及复发饮酒的成功减少是否也降低了主动神经毒性。我们的结果表明，在遗传中选择以发散的戒断严重程度的小鼠戒酒期间的根本明显的神经适应性反应，动物的复发风险增加，对酒精的戒断反应较低。鉴定两个性别中禁欲的途径改变将提供临床上相关的毒品，以帮助开发新型治疗剂，以靶向戒酒的酗酒者的靶向治疗。 公共卫生相关性： 酒精中毒的一个特征是不受控制的酒精消费，其特征是无法避免。饮酒的禁欲是治疗酒精中毒的重要目标，但是对影响复发风险的因素有限，因此很少有有效的治疗方法。我们建议，由于酒精滥用而发生的持续持续性神经适应性基因表达发生了变化，并且取决于基因型/表型，这是戒酒期间复发风险的介体。这些研究的结果将确定用于开发针对靶向治疗的治疗方法，以恢复男性和女性的酗酒者的治疗方法，并可能导致对性别特异性或有针对性治疗的新靶标的，或减轻与慢性乙醇滥用相关的脑损伤的新目标。