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

在过去10年中，女性的酒精使用障碍（AUD）率增加了84%。几 一系列证据表明，女性的饮酒行为更可能是受情感调节的驱使 和压力，而男性饮酒的动机是刺激和酒精相关的正强化。到 迄今为止，还没有一致的努力来开发针对AUD的药物，这些药物针对的因素不同， 保持女性饮酒。使用Koob & Koobow的成瘾循环启发式框架162，我们将针对 “成瘾的黑暗面”，用于开发适合性别的AUD药物。项目1将侧重于一个单一的 去甲肾上腺素能靶点胍法辛，以便充分检查药物对性别的影响 治疗结果。重要的是，项目1将提供一个模板，以机械地评估性别差异 在AUD药物开发中。我们的初步结果表明，胍法辛有力地减少了 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。这种效应的神经机制似乎是性别依赖性的。 对女性来说，胍法辛通过减少压力反应来减少饮酒。对于男性来说，证据不太清楚，但 胍法辛似乎靶向酒精相关的正强化。与耶鲁大学的目标一致- SCORE开发适合性别的AUD治疗方法，并与项目2和3的输入和反馈 领导，我们计划进行第一个，完全动力，机械2b期，双盲，安慰剂对照， 一项平行组研究，旨在检查胍法辛在以下方面的作用的性别差异：1）对抗压力- 实验室中基于刺激的饮酒行为，2）在随后的 治疗阶段。重要的是，我们将研究胍法辛的安全性和潜在的性别差异， 饮酒的潜在机制（例如，渴望，情绪，认知功能，心血管反应， HPA轴活性、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，我们将使用一种创新的生物传感器系统，以评估自然的饮用过程中的6- 周治疗期。据我们所知，这将是第一个前瞻性的临床试验研究， 检查选择性α2a激动剂治疗潜力和相关机制的性别差异， 胍法辛，用于治疗AUD。综合三个项目的调查结果将确定新的 神经生物学靶点的性别适当的治疗AUD。

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.