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

描述（由申请人提供）：酒精滥用仍然是一个公共卫生问题，确定治疗酒精使用障碍的有效药物仍然是NIAAA的高度优先事项。一个有希望的，但相对未探索的途径，药物开发酒精使用的治疗目标是应激反应。几条证据表明，压力是酒精使用和复发的主要媒介。临床前研究表明，去甲肾上腺素能通路参与应激诱导的消费和酒精恢复，以及酒精相关的强化和戒断，并且它们的操纵可能对酒精使用具有潜在的治疗益处。在 一项评估胍法辛（一种α 2A去甲肾上腺素能激动剂）用于戒烟的研究表明，3 mg/天的胍法辛耐受性良好，减弱了压力对吸烟的影响，减少了吸烟相关的强化，改善了认知，并在短暂的治疗阶段显著减少了吸烟。在我们吸烟研究的饮酒者子样本中，胍法辛有力地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。在3周的滴定阶段，药物对饮酒的影响是明显的，并且独立于药物对吸烟行为的影响。我们的研究结果表明，胍法辛应进一步评估作为一个潜在的治疗酒精使用障碍。 对于这一修订后的R 01申请，我们计划建立在我们有希望的试点数据，并进行第二阶段人体实验室研究，评估胍法辛对酒精消费的影响。非寻求治疗的酒精使用障碍成人将随机接受胍法辛治疗（3 mg/天、1.5 mg/天或安慰剂，每个细胞n=50，共n=150），在3周内滴定至稳态水平，然后将完成两次实验室检查，包括诱导应激或中性/放松状态的经过充分验证的方法（顺序平衡），然后是已知对药物作用敏感的2小时酒精自我给药模式。我们假设，与安慰剂（0 mg/天）相比，胍法辛（1.5或3.0 mg/天）将减少自我给药期间消耗的饮料数量，并且这种效果在压力下会更加明显。我们还预计胍法辛在滴定期间和与酒精联合使用时是安全的，耐受性良好，不良事件将是剂量依赖性的。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，证据表明靶向去甲肾上腺素能系统以减少应激反应是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。

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.