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酒精中毒的发展和维持的方式上有所不同。然而，还没有发表的关于酒精依赖患者的研究检验了压力反应的性别差异，这种差异很可能介导了这些影响，并影响了这种疾病的临床病程和治疗。 这项修订后的申请建议扩展我们的初步工作，揭示戒酒者基础和5-羟色胺诱导的应激反应中性别依赖的变化。5-羟色胺调节大脑对某些不可控应激源的反应，在5-羟色胺和下丘脑-垂体-肾上腺(HPA)功能上都存在性别差异。因此，我们的主要目的是确定我们在女性酗酒者身上观察到的超敏和持续的应激反应是否与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，5-羟色胺功能或HPA敏感性的性别差异与遗传影响的5-羟色胺信号变化共同作用，在一些酗酒女性中产生不适应的应激反应。 为了验证这一假设，我们将进行一项随机、双盲、交叉研究，受试者在每月间隔的3个不同的平衡场合接受西酞普兰、地塞米松/促肾上腺皮质激素释放激素和安慰剂的刺激性测试。受试者将被证实戒酒，寻求治疗的女性和男性没有居住在受控清醒生活环境中的共病精神或其他非法物质使用障碍。不酗酒的女性和男性将作为对照，所有组的受试者数量将根据有和没有酗酒家族史的人数进行平衡。受试者的DNA将进行基因分型，以确定5-羟色胺转运体基因启动子区的等位基因变异，这些变异已被发现会影响转运体功能和应激反应。将获得内分泌、行为、心血管和儿茶酚胺应激测量，以及可能影响结果测量的生活应激和不良生活事件的测量。 据我们所知，这将是第一次在酒精依赖患者中同时评估生理性别差异的应激反应、环境生活压力的性别差异以及5-羟色胺转运体的多态性。这些结果应该会通过确定压力反应中潜在的性别差异的机制来推动这一领域的发展，这些机制会影响酒精中毒的易感性，以及对旨在预防或治疗这种疾病的5-羟色胺能药物的反应。

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.