Alcohol and Gender Effects on Stress Circuit Function

描述（由申请人提供）：女性和男性在压力影响酗酒发展和维持的方式上存在差异。然而，没有发表的研究酒精依赖患者的压力反应，最有可能介导这些影响和影响的临床过程和治疗障碍的性别差异进行了检查。 这个修订后的应用程序建议扩展我们的初步工作，揭示了禁欲酗酒者的基础和降钙素诱导的应激反应的性别依赖性改变。5-羟色胺调节大脑对某些无法控制的压力的反应，并且5-羟色胺和下丘脑-垂体-肾上腺（HPA）功能存在性别差异。因此，我们的主要目的是确定我们在女性酗酒者中观察到的超敏和长期应激反应是否与5-羟色胺信号或HPA敏感性的性别差异有关。我们的中心假设是，在某些酗酒女性中，5-羟色胺功能或HPA敏感性的性别差异与5-羟色胺信号传导中受遗传影响的改变合谋产生适应不良的应激反应。 为了检验这一假设，我们将进行一项随机、双盲、交叉研究，受试者每月接受3次西酞普兰、地塞米松/促肾上腺皮质激素释放激素和安慰剂的激发试验。受试者将被验证为禁欲、寻求治疗的酗酒女性和男性，无精神病或其他非法物质使用障碍的共病者，居住在受控的清醒生活环境中。不酗酒的女性和男性将作为对照，所有组将在有和没有酗酒家族史的受试者数量上保持平衡。将对受试者的DNA进行基因分型，以确定5-羟色胺转运蛋白基因启动子区域中的等位基因变体，这些变体已被发现影响转运蛋白功能和应激反应。将获得内分泌、行为、心血管和儿茶酚胺应激指标沿着可能影响结局指标的生活应激和不良生活事件指标。 据我们所知，这将是第一个在酒精依赖患者中进行的研究，同时评估压力反应的生物性别差异，环境生活压力的性别差异和5-羟色胺转运蛋白多态性。这些结果应该通过确定压力反应性性别差异的潜在机制来推动该领域的发展，这些机制影响了酗酒的脆弱性和对旨在预防或治疗这种疾病的药物的反应性。

DESCRIPTION (provided by applicant): Women and men differ in the ways stress affects the development and maintenance of alcoholism. However, no published studies in alcohol dependent patients have examined sex differences in stress responsiveness that most likely mediate these effects and influence the clinical course and treatment of the disorder. This revised application proposes to extend our preliminary work revealing sex-dependent alterations in basal and serotonin-induced stress responses in abstinent alcoholics. Serotonin regulates the brain's response to certain uncontrollable stressors, and there are sex differences in both serotonin and hypothalamic-pituitary-adrenal (HPA) function. Thus, our chief aim is to determine whether the hypersensitive and prolonged stress response we observed in female alcoholics is related to sex differences in serotonin signaling or HPA sensitivity. Our central hypothesis is that sex differences in serotonin function or HPA sensitivity conspire with genetically influenced alterations in serotonin signaling to produce maladaptive stress responses in some alcoholic women. To test this hypothesis, we will perform a randomized, double blind, crossover study where subjects receive provocative tests with citalopram, dexamethasone/corticotropin-releasing hormone and placebo on 3 separate, counterbalanced occasions at monthly intervals. Subjects will be verified abstinent, treatment seeking alcoholic women and men without comorbid psychiatric or other illicit substance use disorders residing in controlled sober living environments. Non-alcoholic women and men will serve as controls, and all groups will be balanced on the number of subjects with and without a family history of alcoholism. Subjects' DNA will be genotyped to determine allelic variants in the promoter region of the serotonin transporter gene that have been found to influence transporter function and stress responsiveness. Endocrine, behavioral, cardiovascular and catecholamine stress measures will be obtained along with measures of life stress and adverse life events that may influence the outcome measures. To our knowledge, this will be the first study conducted in alcohol dependent patients to simultaneously assess biological sex differences in stress responsivity, gender differences in environmental life stress, and the serotonin transporter polymorphism. The results should advance the field by identifying mechanisms underlying sex differences in stress responsiveness that influence vulnerability to develop alcoholism and responsiveness to serotonergic medications intended to prevent or treat the disorder.