PROJECT 1: Targeting stress-reactivity and noradrenergic mechanisms for sex-appropriate alcohol use disorder treatment.

在过去的10年里，女性的酒精使用障碍(AUD)率增加了84%。几个 一系列证据表明，女性的饮酒行为更有可能受到情感控制的推动 和压力，而男性饮酒的动机是刺激和与酒精相关的积极强化。至 到目前为止，还没有共同努力开发针对不同因素的AUD药物 保持女性饮酒。使用Koob&Volkow的成瘾周期启发式框架162，我们将针对 性行为适宜的AUD药物开发的“成瘾的阴暗面”。项目1将专注于单一的 去甲肾上腺素能靶点，鸟粪法新，以便完全有能力通过药物作用来检查性 治疗结果。重要的是，项目1将提供一个模板来机械地评估性别差异 在澳大利亚的药物开发方面。我们的初步结果表明，愈创法新能有效地降低 女性和男性酗酒的数量、频率和百分比， 对女性的影响可能更大。这种效应背后的神经机制似乎与性别有关。 对于女性来说，金刚烷通过减少应激反应来减少饮酒。对于男性来说，证据不那么清楚，但 瓜那法辛似乎针对与酒精相关的阳性强化。与耶鲁大学的目标一致- 在项目2和3的投入和反馈下，为开发针对AUD的性合适疗法进行评分 我们计划进行第一个，全动力，机械化的2b阶段，双盲，安慰剂对照， 一项平行分组研究，以检验愈创方新在以下方面的性别差异：1)对抗压力--和 实验室中基于刺激的饮酒行为和2)在随后的治疗中改善临床结果 治疗阶段。重要的是，我们将检查鸟嘌呤的安全性和潜在的性别差异。 饮酒的机制(例如，渴求、情绪、认知功能、心血管反应性、 HPA轴活动、细胞因子、酒精代谢标志物、性类固醇激素和主观酒精 效果)。此外，我们将使用创新的生物传感器系统来评估6- 疗程为一周。据我们所知，这将是第一次前瞻性的临床试验研究 研究选择性α2a激动剂的治疗潜力和相关机制的性别差异， 愈创新，用于治疗澳门氏症。综合三个项目的调查结果将确定新的 AUD性适宜疗法的神经生物学靶点。

Rates of alcohol use disorders (AUDs) have increased by 84% in women over the past 10 years. Several lines of evidence indicate that drinking behavior in women is more likely to be motivated by affect regulation and stress, whereas drinking in men is motivated by stimulation and alcohol-related positive reinforcement. To date, there has been no concerted effort to develop medications for AUD that target factors which differentially maintain drinking in women. Using Koob & Volkow’s heuristic framework of the addiction cycle162, we will target the ‘dark side of addiction’ for sex-appropriate AUD medication development. Project 1 will focus on a single noradrenergic target, guanfacine, in order to be fully powered to examine sex by medication effects on treatment outcomes. Importantly, Project 1 will provide a template to mechanistically evaluate sex differences in AUD medication development. Our preliminary results demonstrate that guanfacine robustly reduces the quantity, frequency, and percentage of binge episodes of alcohol consumption in both women and men, with possibly larger effects in women. The neural mechanisms underlying this effect appear to be sex-dependent. For women, guanfacine reduces drinking by reducing stress reactivity. For men, the evidence is less clear, but guanfacine appears to target alcohol-related positive reinforcement. Consistent with the aim of the Yale- SCORE to develop sex-appropriate therapeutics for AUD, and with the input and feedback of Project 2 & 3 Leads, we plan to conduct the first, fully-powered, mechanistic Phase 2b, double-blind, placebo-controlled, parallel-group study to examine sex differences in guanfacine's effect on: 1) counteracting stress- and stimulation-based drinking behavior in the laboratory and 2) improving clinical outcomes during a subsequent treatment phase. Importantly, we will examine the safety of guanfacine and potential sex differences in mechanisms underlying drinking (e.g., craving, mood, cognitive function, cardiovascular reactivity, markers of HPA-axis activity, cytokines, markers of alcohol-metabolism, sex steroid hormones, and subjective alcohol effects). Additionally, we will use an innovative biosensor system to assess naturalistic drinking during the 6- week treatment period. To our knowledge, this will be the first clinical trial investigation to prospectively examine sex differences in the therapeutic potential and associated mechanisms of a selective α2a agonist, guanfacine, for the treatment of AUD. Synthesis of findings across the three projects will identify new neurobiological targets for sex-appropriate therapeutics for AUD.