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

项目总结/摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，复发率高， 非常需要开发和评估新的治疗方法以降低复发率和相关的 澳元的负担。本申请提出了一种新的，机制结合实验室和临床结果 研究是否神经活性类固醇前体孕烯醇酮（PREG）通过其转化为 有效的GABA能神经活性类固醇Allopregnanolone（ALLO）减少了引起的酒精渴望， 焦虑，使压力失调正常化，并改善认知灵活性和酒精使用结果， 寻求治疗的AUD患者。我们小组和其他人以前的研究表明， 酒精滥用使包括下丘脑-垂体-肾上腺（HPA）轴在内的脑应激通路失调 反应并与高激发的酒精渴望、焦虑和认知灵活性相关，而这些反过来又是 预测随后的酒精复发和临床结果。从我们的研究中， 实验室表明，通过给予ALLO前体（包括PREG）增强ALLO， 这种压力相关的中断和减少酒精渴望和复发的风险。然而， 什么PREG，以及它可能降低酒精渴望和复发风险的具体剂量， 不知道。在这些发现的基础上，我们提出了一个概念验证的4年，随机，双盲，剂量 独立的实验室和临床研究，以评估PREG治疗的初步疗效（200/400 在90名AUD男性和女性中，将其与安慰剂（PBO）进行比较。以下具体目标将是 目的1：评价200 mg和400 mg/天PREG在AUD个体中的安全性/耐受性。 目标2a：评估PREG剂量（PBO，200和400 mg/天）对ALLO水平和对 在AUD患者中实验性地激发了渴望、HPA失调、焦虑、情绪和认知灵活性。 目的2b：评估PREG刺激的ALLO水平是否介导其对激发的渴望、HPA 失调，焦虑，情绪和认知灵活性的实验室组成部分。目标3a：评估 8周PREG剂量与PBO治疗对初级酒精使用结局的初步疗效， 酒精渴望、焦虑和消极情绪的次要结果。目标3b：评估PREG- 刺激的ALLO水平介导其对初级酒精使用结果和二级临床 8周治疗期间的结果。探索性目的：探索治疗前患者是否 特征（性别、酒精中毒（FH）家族史、创伤史和共病药物使用）的影响 PREG增强的ALLO水平与初级和二级酒精使用结果成功完成 提出的目标有可能支持进一步开发新的神经活性类固醇靶点， 作为PREG和ALLO治疗AUD，特别是针对慢性酒精相关应激失调， 酒精渴望和高酒精复发风险。

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.