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

8/8：INIA 压力和慢性酒精相互作用：重度饮酒者中的糖皮质激素拮抗剂：对功能磁共振成像连接、戒断和饮酒的影响

• 批准号: 9242249
• 负责人: MARY E MCCAUL
• 金额: $ 41.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242249
• 关键词: Abstinence; Acute; Adverse effects; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic beverage heavy drinker; Alcohols; Amygdaloid structure; Area; Attenuated; Behavior; Brain; Brain region; Chronic; Clinical Research; Consumption; Development; Dopamine; Effectiveness; Endocrine System Diseases; Environment; FDA approved; Functional Magnetic Resonance Imaging; Glucocorticoid Receptor; Glucocorticoids; Grant; Heart Rate; Hormones; Human; Hydrocortisone; Hypertension; Hypokalemia; Investigational Therapies; Laboratories; Laboratory Procedures; Measures; Mental disorders; Mifepristone; Moods; Motivation; Nucleus Accumbens; Pathway interactions; Patient Self-Report; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Placebos; Play; Prefrontal Cortex; Progesterone Receptors; Progress Reports; Randomized; Receptor Gene; Recording of previous events; Relapse; Reporting; Research; Rest; Rewards; Risk; Rodent; Role; Safety; Scanning; Self Administration; Severities; Signal Transduction; Skin Temperature; Stress; Supervision; Symptoms; System; Termination of pregnancy; Testing; Withdrawal; Withdrawal Symptom; Woman; Work; alcohol abstinence; alcohol behavior; alcohol craving; alcohol cue; alcohol exposure; alcohol measurement; alcohol reward; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; craving; drinking; drug reward; functional MRI scan; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; healing; human study; improved; men; negative mood; pre-clinical; receptor; receptor binding; research study; response; secondary analysis; social stress; stressor

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.

皮质醇（CORT）是一种糖皮质激素，通常与应激反应有关，在