Does Guanfacine, an alpha2 adrenergic agonist, attenuate stress-induced drinking?

胍法辛（一种 α2 肾上腺素能激动剂）是否可以减轻压力引起的饮酒？

• 批准号: 8631313
• 负责人: SHERRY ANN MCKEE
• 金额: $ 37.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631313
• 关键词: Adrenergic Agonists; Adult; Adverse event; Agonist; Alcohol consumption; Alcohols; Anxiety; Area; Attention; Attenuated; Behavior Control; Blood Pressure; Cardiovascular system; Catecholamines; Cells; Cognition; Consumption; Corticotropin; DSM-IV; Data; Dependence; Development; Dizziness; Dose; Double-Blind Method; Environment; Frequencies; Future; Guanfacine; Heart Rate; Heavy Drinking; Hour; Human; Hydrocortisone; Imagery; Investigation; Laboratories; Laboratory Study; Mediating; Mediator of activation protein; Methods; National Institute on Alcohol Abuse and Alcoholism; Nausea; Negative Reinforcements; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebo Control; Placebos; Population; Prefrontal Cortex; Psychological reinforcement; Public Health; Randomized; Research; Research Priority; Safety; Sedation procedure; Self Administration; Short-Term Memory; Smoking; Smoking Behavior; Stress; Symptoms; System; Therapeutic; Titrations; Withdrawal; Woman; alcohol craving; alcohol effect; alcohol misuse; alcohol relapse; alcohol use disorder; brief intervention; cognitive function; cost; design; drinking; drinking behavior; drug of abuse; improved; meetings; men; negative mood; noradrenergic; pre-clinical research; preclinical study; public health relevance; receptor; smoking cessation; therapeutic target; trait

DESCRIPTION (provided by applicant): Alcohol misuse continues to be a public health problem and identifying effective medications for the treatment of alcohol use disorders remains a high priority for NIAAA. One promising, yet relatively unexplored avenue for medication development for alcohol use are therapeutics that target stress-reactivity. Several lines of evidence suggest that stress is a primary mediator of alcohol use and relapse. Preclinical research demonstrates that noradrenergic pathways are involved in stress-induced consumption and reinstatement to alcohol, as well as alcohol-related reinforcement and withdrawal, and that their manipulation may be of potential therapeutic benefit for alcohol use. In a study evaluating guanfacine, an alpha2a noradrenergic agonist, for smoking cessation we demonstrated that 3mg/day guanfacine was well tolerated, attenuated the effects of stress on smoking, reduced smoking-related reinforcement, improved cognition, and significantly reduced smoking during a brief treatment phase. In a subsample of drinkers from our smoking study, guanfacine robustly reduced the quantity and frequency of alcohol consumption, reduced the frequency of binge consumption, and improved cognition. Medication effects on drinking were evident during the 3-week titration phase, and were independent of medication effects on smoking behavior. Our results suggest that guanfacine should be further evaluated as a potential treatment for alcohol use disorders. For this revised R01 application, we plan to build upon our promising pilot data and conduct the first Phase II human laboratory study evaluating the effect of guanfacine on alcohol consumption. Non-treatment seeking adults with alcohol use disorders will be randomized to guanfacine (3mg/day, 1.5mg/day, or placebo, n=50 per cell, n=150 total), titrated to steady state levels over a 3-week period, and will then complete two laboratory sessions consisting of a well validated method for inducing a stress or neutral/relaxing state (order counterbalanced), followed by a 2-hour alcohol self-administration paradigm known to be sensitive to medication effects. We hypothesize that guanfacine (1.5, or 3.0mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and that this effect will be more pronounced following stress. We also expect that guanfacine will be safe and well tolerated during the titration period and in combination with alcohol, and that adverse events will be dose-dependent. Results will provide important information concerning dose selection for future Phase II clinical trial investigations, evidence that targeting the noradrenergic system to reduce stress reactivity is a viable medication development strategy for alcohol use disorders, and elucidate potential mechanisms for these effects.

描述（由申请人提供）：酒精滥用仍然是一个公共卫生问题，识别治疗酒精使用障碍的有效药物仍然是 NIAAA 的高度优先事项。针对酒精使用的药物开发的一种有前途但相对尚未探索的途径是针对应激反应的治疗方法。多项证据表明，压力是饮酒和复吸的主要因素。临床前研究表明，去甲肾上腺素能途径参与压力诱导的饮酒和恢复饮酒，以及与酒精相关的强化和戒断，并且它们的操纵可能对饮酒具有潜在的治疗益处。在 一项评估胍法辛（一种 α2a 去甲肾上腺素能激动剂）戒烟效果的研究表明，3 毫克/天的胍法辛具有良好的耐受性，可以减轻压力对吸烟的影响，减少与吸烟相关的强化，改善认知，并在短暂的治疗阶段显着减少吸烟。在我们吸烟研究的饮酒者子样本中，胍法辛显着减少了饮酒的数量和频率，减少了暴饮暴食的频率，并改善了认知能力。在 3 周滴定阶段，药物对饮酒的影响很明显，并且与药物对吸烟行为的影响无关。我们的结果表明，应该进一步评估胍法辛作为酒精使用障碍的潜在治疗方法。 对于这一修订后的 R01 申请，我们计划以我们有希望的试点数据为基础，进行第一个 II 期人体实验室研究，评估胍法辛对饮酒的影响。患有酒精使用障碍的未寻求治疗的成年人将被随机服用胍法辛（3 毫克/天、1.5 毫克/天或安慰剂，每个细胞 n = 50，总共 n = 150），在 3 周内滴定至稳态水平，然后将完成两个实验室课程，包括经过充分验证的诱导压力或中性/放松状态的方法（顺序平衡），然后是 2 小时饮酒 已知对药物作用敏感的自我给药模式。我们假设，与安慰剂（0 毫克/天）相比，胍法辛（1.5 或 3.0 毫克/天）会减少自我给药期间饮用的饮料数量，并且这种效果在压力后会更加明显。我们还预计胍法辛在滴定期间以及与酒精合用时是安全的且具有良好的耐受性，并且不良事件将呈剂量依赖性。结果将为未来的 II 期临床试验研究提供有关剂量选择的重要信息，证明以去甲肾上腺素能系统减少应激反应性是治疗酒精使用障碍的可行药物开发策略，并阐明这些作用的潜在机制。