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10年中，女性酒精使用障碍（AUDs）的发生率增加了84%。几个