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.

过去 10 年来，女性酒精使用障碍 (AUD) 率增加了 84%。 一系列证据表明，女性的饮酒行为更有可能受到情感调节的推动 和压力，而男性饮酒是由刺激和与酒精相关的正强化驱动的。 迄今为止，还没有共同努力开发针对不同因素的 AUD 药物。 利用 Koob 和 Volkow 的成瘾周期启发式框架 162，我们将目标定为保持女性饮酒。 适合性别的 AUD 药物开发的“成瘾的阴暗面”项目 1 将重点关注单一药物。 去甲肾上腺素能靶点，胍法辛，以便充分通过药物作用来检查性别 重要的是，项目 1 将提供一个模板来机械地评估性别差异。 我们的初步结果表明，胍法辛可显着降低 AUD 药物开发的风险。 女性和男性酗酒的数量、频率和百分比， 这种效应的神经机制似乎与性别有关。 对于女性来说，饮用胍法辛可以减少压力反应。对于男性来说，证据尚不明确，但是。 胍法辛似乎针对与酒精相关的积极强化，这与耶鲁大学的目标一致。 SCORE 为 AUD 开发适合性别的疗法，并根据项目 2 和 3 的意见和反馈 我们计划进行第一个全动力机械阶段 2b、双盲、安慰剂控制、 平行组研究检查胍法辛作用的性别差异：1）抵消压力和 实验室中基于刺激的饮酒行为，以及 2) 改善随后的临床结果 重要的是，我们将检查胍法辛的安全性和潜在的性别差异。 饮酒背后的机制（例如渴望、情绪、认知功能、心血管反应性、饮酒标志物） 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 此外，我们将使用创新的生物传感器系统来评估 6- 据我们所知，这将是第一个前瞻性临床试验研究。 检查选择性 α2a 激动剂的治疗潜力和相关机制的性别差异， 胍法辛用于治疗 AUD 三个项目的研究结果的综合将确定新的。 AUD 性别适宜治疗的神经生物学目标。