Effect of allopregnanolone on stress-induced craving

项目摘要/摘要 压力系统失调在酒精使用病因学中的重要性一直被认为 已经建立，并一直在寻找参与这一过程的调节器和机制 这是一个正在进行的研究目标。神经类固醇被认为是压力调节的中心。 反应和最近的证据表明，一种新的神经类固醇，别孕酮调节酒精 强化、宽容、依赖和退缩。我们建议详细说明这一角色，以及 别孕酮抗酒精作用机制的研究 别孕酮减轻应激诱导的酒精渴求、应激诱导的焦虑和主观感觉 使用实验室范例研究酒精的兴奋/镇静作用。的次要目标 本项目旨在研究别孕酮的行为效应。这是一种双盲， 安慰剂对照，受试者之间的研究，在没有寻求治疗的AUD患者中。全 参与者将接受单剂别孕酮的持续输注(160分钟) (靶向剂量100 NM)或安慰剂。在单一测试日，在输液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提示将在 随机顺序。压力引起的渴望和压力引起的焦虑的测量将在 球杆(Pre)，紧跟在球杆(POST)之后和球杆(恢复)后10分钟。在.期间 前60分钟。评估情绪、认知和运动协调性的输液措施将 管理。所有参与者还将接受静脉注射酒精，使用 一种夹闭程序，目标是呼气酒精浓度(BRAC)为40 mg%(40 Mg/dL)。酒精将在脚本演示后给予(距离目标20分钟 并夹紧额外的30分钟)。 该项目的主要目的是检查别孕酮作为一种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求、焦虑和主观兴奋/镇静作用方面的作用 实验室里的酒精。这项研究是第一次考察阿司匹林的治疗潜力。 别孕酮及其可能治疗酒精使用障碍的作用机制。

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.