Expression Differences During Abstinence Predict Risk Of Alcohol Relapse

描述(由申请人提供)： 酒精中毒是一种慢性复发性疾病，与戒酒一段时间后的过度消费有关。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，但在戒酒中表现不佳。我们认为，识别戒酒期间前额叶皮质中改变的通路，将提供与男女复发风险相关的信息。前额叶皮质是与酗酒者认知功能障碍和损害相关的大脑区域。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，包括戒断癫痫抵抗(WSR)和戒断癫痫易感(WSP)选择的品系。为了将结果集中于表型特异性的表达差异分析，还将使用第二个具有不同戒断反应的模型，即近交系C57BL/6J与DBA/2J小鼠品系。雄性和雌性小鼠长期暴露在高度醉人的乙醇浓度中，然后停用，然后保持禁欲21天。将采取系统的方法来表征在调节复发风险方面具有重要意义的显著表达差异，有三个具体目标。特定目的1将使用高密度转录图谱和生物信息学分析来识别在戒断过程中显著改变的依赖于戒断反应表型的新途径。第二个目标将使用戒断诱导的复发增加的反复饮酒模型来对表达差异进行行为验证，从功能上测试已识别的影响复发的途径的能力。第三个目标将确定在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，以及成功减少反复饮酒是否也减少了主动神经毒性。我们的结果表明，在戒酒严重程度不同的基因选择的小鼠中，禁欲期间有一种根本不同的神经适应反应，对酒精的戒断反应低的动物复发的风险增加。识别男女戒酒过程中改变的途径将提供临床上相关的TOOS，以帮助开发新的治疗方法，用于靶向治疗戒酒患者亚群的复发。

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 Male and female mice are chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days.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.