Effect of allopregnanolone on stress-induced craving

四氢孕酮对压力引起的渴望的影响

• 批准号: 9560669
• 负责人: Elizabeth Ralevski
• 金额: $ 18.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9560669
• 关键词: Acids; Alcohol consumption; Alcohol dependence; Alcohols; Allopregnanolone; Analgesics; Anti-Anxiety Agents; Antiepileptic Agents; Anxiety; Area; Attenuated; Behavioral; Brain; Calcium Channel; Clinical; Clinical Trials; Closure by clamp; Cognition; Cognitive; Comorbidity; Consumption; Continuous Infusion; Cues; Data; Dependence; Development; Dose; Double-Blind Method; Equipment and supply inventories; Etiology; Future; Gender; Glutamates; Glycine Receptors; Goals; Human; Individual; Infusion procedures; Intravenous; Intravenous infusion procedures; Laboratories; Lead; Literature; Maintenance; Measures; Mediating; Memory; Moods; Motor; Neuraxis; Nicotinic Receptors; Outcome; Outcome Measure; Participant; Placebos; Play; Potassium Channel; Procedures; Process; Property; Questionnaires; Randomized; Recovery; Regulation; Research; Rewards; Role; Safety; Section 8; Stress; Study Subject; Substance Use Disorder; System; Testing; Therapeutic; Verbal Learning; Withdrawal; Work; addiction; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol reinforcement; alcohol reward; alcohol seeking behavior; alcohol use disorder; biological adaptation to stress; breath alcohol measurement; cognitive function; cognitive performance; craving; drinking; drug of abuse; efficacy testing; experience; hypothalamic-pituitary-adrenal axis; interest; laboratory experiment; neurosteroids; phase 1 study; placebo controlled study; receptor; response; secondary outcome; sedative; trait

Project Summary/Abstract The importance of the stress-system dysregulation in the etiology of alcohol use has long been established, and the search for modulators and mechanisms that are involved in this process has been an ongoing goal of research. Neurosteroids are considered central in the regulation of the stress response and recent evidence suggests that a new neurosteroid, allopregnanolone mediates alcohol reinforcement, tolerance, dependence and withdrawal. We propose to explicate the role, and the mechanisms of allopregnanolone on alcohol effects by determining whether intravenous infusion of allopregnanolone attenuates stress-induced alcohol craving, stress-induced anxiety, and subjective stimulant/sedative effects of alcohol using a laboratory paradigm. The secondary objective of this project is to characterize the behavioral effects of allopregnanolone. This is a double-blind, placebo-controlled, between-subjects study in non-treatment seeking individuals with AUD. All participants will receive a continuous infusion (160 minutes) of a single dose of allopregnanolone (targeted dose 100 nM) or placebo. On a single test day, after 60 min of infusion - when ALLO levels stabilize - stress and neutral cues consisting of personalized 5 minutes scripts will be presented in random order. Measures of stress-induced craving and stress-induced anxiety will be collected before the cue (pre), immediately following the cue (post) and 10 min after (recovery) the cue. During the first 60 min. of infusion measures evaluating mood, cognition and motor coordination will be administered. All participants will also receive alcohol administered intravenously using a clamp procedure, targeting a breath alcohol concentration (BrAc) of 40mg% (40 mg/dL). Alcohol will be administered following script presentation (20 min to target and clamped for additional 30min). The main aim of this project is to examine the safety and efficacy of allopregnanolone as a possible treatment for alcohol use disorders. We wish to determine if allopregnanolone is superior to placebo in reducing alcohol craving, anxiety and subjective stimulant/sedative effects of alcohol in the laboratory. This study is the first to examine the therapeutic potential of allopregnanolone and its mechanism of action as a possible treatment for alcohol use disorders.

项目概要/摘要 压力系统失调在饮酒病因学中的重要性长期以来一直被认为 已经建立，并且已经开始寻找参与该过程的调节剂和机制 一个持续的研究目标。神经类固醇被认为是调节压力的核心 反应和最近的证据表明，一种新的神经类固醇，四氢孕酮可以介导酒精 强化、耐受、依赖和退缩。我们建议阐明这一角色，以及 通过确定是否静脉输注四异孕酮对酒精影响的机制 四氢孕酮可减轻压力引起的酒精渴望、压力引起的焦虑和主观情绪 使用实验室范例研究酒精的兴奋/镇静作用。次要目标 该项目旨在表征四氢孕酮的行为效应。这是双盲， 对未寻求治疗的 AUD 患者进行安慰剂对照、受试者间研究。全部 参与者将接受单剂量四氢孕酮的连续输注（160 分钟） （目标剂量 100 nM）或安慰剂。在单个测试日，输注 60 分钟后 - 当 ALLO 水平 稳定 - 由个性化的 5 分钟脚本组成的压力和中性线索将在 随机顺序。压力引起的渴望和压力引起的焦虑的测量将在之前收集 提示（前）、提示后立即（后）以及提示后 10 分钟（恢复）。期间 前 60 分钟评估情绪、认知和运动协调性的输注措施将 管理。所有参与者还将接受静脉注射酒精 钳夹程序，目标呼吸酒精浓度 (BrAc) 为 40mg%（40 毫克/分升）。剧本呈现后将进行酒精注射（20 分钟达到目标） 并夹紧另外30分钟）。 该项目的主要目的是检查四氢孕酮作为药物的安全性和有效性。 酒精使用障碍的可能治疗方法。我们希望确定别孕酮是否优于 安慰剂在减少酒精渴望、焦虑和主观兴奋/镇静作用方面 实验室里的酒精。这项研究是第一个检验其治疗潜力的研究 别孕酮及其作为酒精使用障碍的可能治疗方法的作用机制。