Effect of allopregnanolone on stress-induced craving

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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.