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

项目 1：针对压力反应性和去甲肾上腺素能机制，进行适合性别的酒精使用障碍治疗。

• 批准号: 10599822
• 负责人: SHERRY ANN MCKEE
• 金额: $ 27.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599822
• 关键词: Address; Adrenergic Agonists; Adrenergic Receptor; Affect; Agonist; Alcohol consumption; Alcohols; Attenuated; Behavior; Biosensor; Blood alcohol level measurement; Cardiovascular system; Cellular Phone; Clinical; Clinical Trials; Clinical Trials Design; Consumption; Corticotropin; Darkness; Data; Development; Double-Blind Method; Ethanol Metabolism; FDA approved; Feedback; Female; Frequencies; Germ Cells; Gonadal Steroid Hormones; Grant; Guanfacine; Heavy Drinking; Human; Hybrids; Hydrocortisone; Imagery; Investigation; Laboratories; Location; Moods; Negative Reinforcements; Neurobiology; Norepinephrine; Outcome; Participant; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Positive Reinforcements; Pre-Clinical Model; Property; Prospective Studies; Public Health; Randomized; Regulation; Relapse; Research; Resources; Rewards; Safety; Sex Differences; Side; Stress; System; Therapeutic; Time; Titrations; Treatment outcome; Woman; addiction; alcohol abuse therapy; alcohol effect; alcohol use disorder; cognitive function; craving; cytokine; design; drinking; drinking behavior; heuristics; hypothalamic-pituitary-adrenal axis; improved; innovation; male; men; neuromechanism; noradrenergic; novel; presynaptic; prospective; sex; social; stress reactivity; stress reduction; treatment duration; wearable sensor technology

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.

在过去的10年中，女性的酒精使用障碍率（AUD）增加了84％。一些 证据表明，女性的饮酒行为更有可能受到影响调节的动机 和压力，而男性的饮酒是由刺激和与酒精相关的阳性增强的动机。到 日期，没有共同努力为AUD开发药物，而这些因素是差异化因素 维持女性饮酒。使用Koob＆Volkow的成瘾周期的启发式框架162，我们将针对 适合性别的AUD药物开发的“成瘾的黑暗面”。项目1将重点放在一个 去甲肾上腺素靶标，鸟法汀，以便通过对药物的影响进行全力检查性行为 治疗结果。重要的是，项目1将提供一个模板来机械评估性别差异 在AUD药物开发中。我们的初步结果表明，鸟汀可稳健地减少 男性和男性的饮酒狂热量的数量，频率和百分比， 女性的影响更大。这种作用的神经机制似乎是性别依赖性的。 对于女性，鸟宁通过降低压力反应性来减少饮酒。对于男人来说，证据不太清楚，但是 鸟宁似乎靶向与酒精相关的阳性增强。与耶鲁的目标一致 得分以开发适合AUD的性别疗法，并随着项目2和3的投入和反馈 线索，我们计划进行第一个，完全供电的机械阶段2B，双盲，安慰剂对照， 平行组研究，以检查鸟法素对：1）应激和应力的影响的性别差异 实验室中基于刺激的饮酒行为，2）在随后的情况下改善临床结果 治疗阶段。重要的是，我们将研究鸟法的安全性和潜在的性别差异 饮酒的基础机制（例如，渴望，情绪，认知功能，心血管反应性，标记 HPA轴活动，细胞因子，酒精代谢的标志，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-- 一周治疗期。据我们所知，这将是前瞻性的首次临床试验调查 检查选择性α2a激动剂的治疗潜力和相关机制的性别差异， 瓜素，用于治疗AUD。在这三个项目中的发现的综合将确定新的 AUD的性行为治疗的神经生物学靶标。