8/8: INIA Stress and Chronic Alcohol Interactions: Glucocorticoid antagonists in heavy drinkers:effects on fMRI connectivity, withdrawal and drinking

皮质醇(Cortiol，CORT)是一种糖皮质激素，常与应激反应有关，在 酒精使用和问题。首先，急性酒精摄入增加了皮质醇，这反过来又放大了 中脑边缘多巴胺奖励信号。第二，戒酒可提高澳大利亚的皮质醇水平。 健康对照受试者和早期戒酒的皮质醇水平预示着随后的饮酒复发。最后， CORT对外部应激源反应的大小预测工作动机和消费 人体实验室和自然环境中的酒精。重要的是，最近对啮齿动物和 人类已经证明，使用糖皮质激素受体(GR)拮抗剂可以阻断皮质醇的活性 减少皮质醇对酒精行为的影响，表明糖皮质激素在这些行为中的因果作用 两性关系。这项拟议的研究将测试两种糖皮质激素受体拮抗剂的有效性 不同的受体结合和副作用。酒精使用障碍(AUD)患者和匹配的健康对照组 (HC)男性和女性，拟议的研究检查了MIFE，并证明了临床前对 与饮酒相关的行为，以及CORT125134，一种安全性得到改善但尚未得到改善的新药 在一系列与酒精相关的措施上，对AUD的疗效未经检验。所有受试者将被随机分配到 每日生活，CORT125134或安慰剂。AUD和HC受试者在服药前和服药期间接受功能磁共振检查 扫描测量静息状态功能连通性和酒精线索诱导的脑激活 大脑奖赏和应激途径。所有受试者均被纳入临床研究单位；AUD受试者 接受监督戒酒，每天测量酒精渴求和症状严重程度。 通过对AUD受试者进行验证的人体实验程序，我们检验了压力对动机的影响。 饮酒和酒精敏感性/奖赏作为GR拮抗的函数。这项工作将有助于为 改进的药物治疗针对大脑中参与启动和奖励的应激和奖励通路 保持饮酒。

Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and playing a key role in alcohol use and problems. First, acute alcohol administration increases CORT, which in turn amplifies the mesolimbic dopamine reward signal. Second, alcohol withdrawal elevates CORT levels in AUD compared with healthy control subjects, and CORT levels in early abstinence predict subsequent relapse to drinking. Finally, the magnitude of CORT response to external stressors predicts motivation to work for and consumption of alcohol in the human laboratory and in the natural environment. Importantly, recent studies in rodents and humans have demonstrated that blocking CORT activity using a glucocorticoid receptor (GR) antagonist reduces these effects of CORT on alcohol behaviors, indicating a causal role for glucocorticoids in these relationships. The proposed research will test the effectiveness of two glucocorticoid receptor antagonists with different receptor binding and side-effect profiles. In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed research examines MIFE, with demonstrated preclinical effects on drinking-related behaviors, and CORT125134, a newer medication with improved safety profile but as yet unexamined efficacy for AUD, on a breadth of alcohol-related measures. All subjects will be randomized to daily MIFE, CORT125134 or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and alcohol cue-induced brain activation focused on brain reward and stress pathways. All subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of alcohol craving and symptom severity. Using validated human laboratory procedures in AUD subjects, we examine the effects of stress on motivation to drink and alcohol sensitivity/reward as a function of GR antagonism. This work will help pave the way for improved pharmacotherapies that target stress and reward pathways in the brain involved in initiating and maintaining drinking.