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，与戒酒后过度饮酒有关。大脑结构、可塑性和基因表达的神经适应性发生于慢性中毒，但在戒断中表现不佳。我们建议，识别前额叶皮层（一个与认知功能障碍和酗酒者损伤相关的大脑区域）禁欲期间改变的通路，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，采用对酒精戒断具有广泛不同反应的动物模型，包括戒断性癫痫抗性（WSR）和戒断性癫痫倾向（WSP）选择的品系。为了集中表达差异的表型特异性分析的结果，还将使用具有不同戒断反应的第二种模型，近交系C57 BL/6 J与DBA/2 J小鼠的品系。雄性和雌性小鼠长期暴露于高度致醉浓度的乙醇中并退出，然后禁欲21天。将采取系统的方法来表征在介导复发风险中重要的显著表达差异，具有三个具体目标。具体目标1将采用高密度cDNA转录谱分析和生物信息学分析，以确定依赖于戒断反应表型的戒断期间显著改变的新途径。第二个目标将在功能上测试所确定的途径影响复发的能力，使用戒断诱导复发模型，提高复发饮酒的行为验证表达差异。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，以及成功减少复发饮酒是否也会减少主动神经毒性。我们的研究结果表明，从基因上选择不同的戒断严重程度的小鼠在禁欲期间有一种根本不同的神经适应性反应，对酒精有低戒断反应的动物复发风险增加。确定男女戒酒途径的改变，将提供临床相关的工具，以帮助开发新的治疗方法，有针对性地治疗戒酒酗酒者的复发。

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 Male and female mice are chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days.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