Neuroactive Steroid Potentiation to Decrease Alcohol Craving, Normalize HPA axis function and Prevent Alcohol Relapse

项目摘要/摘要 酒精使用障碍(AUD)是一种与高复发率相关的慢性复发性疾病，在这种疾病中 非常需要开发和评估新的治疗方法来降低复发率和相关的 澳元的负担。这项应用提出了一种新的、机械性的结合实验室和临床的结果 研究检查神经活性类固醇前体孕烯醇酮(PREG)是否通过其转化为 强效GABA能神经活性类固醇(ALLO)可降低酒精渴求和 焦虑，正常化压力失调，改善认知灵活性和酒精使用结果 寻求治疗的澳元患者。我们小组和其他人之前的研究表明，慢性 酒精滥用使包括下丘脑-垂体-肾上腺(HPA)轴在内的大脑应激途径失调 并与高酒精渴望、焦虑和认知灵活性相关，这些反过来又是 预测随后的酒精复发和临床结果。有希望的新的初步发现来自我们的 实验室表明，通过给予包括PREG在内的前体来增强ALLO可能会逆转 这类压力相关的干扰，并减少酒精渴望和复发的风险。然而，这一机制通过 哪种PREG，以及它可能降低酒精渴求和复发风险的具体剂量是什么 不知道。在这些发现的基础上，我们提出了一个为期4年的概念验证、随机、双盲剂量。 依赖实验室和临床研究以评估PREG治疗的初步疗效(200/400 在90名AUD男性和女性中，每天服用2毫克，连续8周)与安慰剂(PBO)对照。以下是具体目标 目的：1：评估每日服用200 mg和400 mg PREG的AUD患者的安全性和耐受性。 目的2a：评价PREG剂量(PBO，200和400 mg/天)对ALLO水平和 实验引发了AUD患者的渴望、HPA失调、焦虑、情绪和认知灵活性。 目的2b：评估PREG刺激的等位基因水平是否在其刺激的渴求，HPA中起中介作用 实验室成分中的调节失调、焦虑、情绪和认知灵活性。目标3a：评估 8周剂量的PREG与PBO治疗对初次酒精使用结果和 酒精渴求、焦虑和消极情绪的次要结果。目标3b：评估PREG- 刺激的等位基因水平调节其对初次酒精使用结果和二次临床的影响 在8周的治疗阶段中的结果。探索性目的：探讨治疗前患者 特征(性别、酗酒(FH)家族史、精神创伤史和共病吸毒)的影响 孕激素增强的等位基因水平以及初次和二次饮酒的结果。成功完成 拟议的AIMS具有支持进一步开发新的神经活性类固醇靶标的潜力 作为PREG和ALLO在治疗AUD方面，特别是针对慢性酒精相关的应激障碍， 酒精渴求和高酒精复发的风险。

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse and in which there is great need to develop and evaluate novel treatments to decrease relapse rates and the associated burden of AUD. This application proposes a novel, mechanistic combined laboratory and clinical outcome study to examine whether the neuroactive steroid precursor Pregnenolone (PREG) via its conversion to the potent GABAergic neuroactive steroid Allopregnanolone (ALLO) decreases provoked alcohol craving and anxiety, normalizes stress dysregulation, and improves cognitive flexibility and alcohol use outcomes in treatment seeking individuals with AUD. Previous research by our group and others has shown that chronic alcohol abuse dysregulates brain stress pathways including the hypothalamic pituitary adrenal (HPA) axis responses and is associated high provoked alcohol craving, anxiety, and cognitive flexibility, which in turn, are predictive of subsequent alcohol relapse and clinical outcomes. Promising new preliminary findings from our laboratory indicate that potentiating ALLO via administration of its precursors, including PREG, may reverse such stress-related disruptions and decrease alcohol craving and relapse risk. However, the mechanism by which PREG, and the specific doses at which it may potentially decrease alcohol craving and relapse risk is not known. On the basis of these findings, we propose a proof-of-concept 4-year, randomized, double-blind, dose dependent laboratory and clinical study to evaluate the preliminary efficacy of PREG treatment (200/400 mg/day for 8 weeks) versus placebo (PBO) in 90 AUD men and women. The following specific aims will be addressed: Aim 1: To evaluate the safety/tolerability of 200mg and 400mg/daily of PREG in AUD individuals. Aim 2a: To evaluate the effects of PREG doses (PBO, 200 and 400 mg/day) on ALLO levels and on experimentally provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in AUD patients. Aim 2b: To assess whether PREG-stimulated ALLO levels mediate its effects on provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in the laboratory component. Aim 3a: To assess the preliminary efficacy of 8-week PREG doses versus PBO treatment on primary alcohol use outcomes and secondary outcomes of alcohol craving, anxiety and negative mood. Aim 3b: To assess whether PREG- stimulated ALLO levels mediate its effects on primary alcohol use outcomes and on secondary clinical outcomes during the 8-week treatment phase. Exploratory Aim: To explore whether pre-treatment patient characteristics (gender, family history of alcoholism (FH), trauma history and co-morbid drug use) influence PREG-potentiated ALLO levels and primary and secondary alcohol use outcomes. Successful completion of the proposed aims has the potential to support further development of novel neuroactive steroid targets such as PREG and ALLO in the treatment of AUD, particularly to target chronic alcohol-related stress dysregulation, alcohol craving and high alcohol relapse risk.