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，寻找治疗酒精使用障碍的有效药物仍然是NIAAA的高度优先事项。针对应激反应的疗法是开发酒精用药的一个有希望的、但相对未被探索的途径。有几条证据表明，压力是酒精使用和复发的主要中介。临床前研究表明，去甲肾上腺素通路参与应激诱导的饮酒和酒精的恢复，以及与酒精相关的强化和戒断，它们的操纵可能对酒精使用具有潜在的治疗益处。在……里面 一项评估α2a去甲肾上腺素能激动剂瓜那法辛戒烟作用的研究表明，每天3毫克的瓜那法辛耐受性良好，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著减少吸烟。在我们吸烟研究中的一组饮酒者中，愈创法辛有力地减少了饮酒的数量和频率，减少了酗酒的频率，并改善了认知能力。在3周的滴定阶段，药物对饮酒的影响是明显的，并且与药物对吸烟行为的影响无关。我们的结果表明，鸟嘌呤应该被进一步评估为酒精使用障碍的潜在治疗方法。对于这一修订的R01应用，我们计划在我们有希望的试验数据的基础上，进行第一阶段的人体实验室研究，评估瓜那法辛对酒精消费的影响。未寻求治疗的患有酒精使用障碍的成年人将被随机给予胍法辛(3毫克/天，1.5毫克/天，或安慰剂，每个细胞50个，总共150个)，在3周内滴定到稳定水平，然后将完成两个实验室疗程，其中包括一个经过充分验证的诱导压力或中性/放松状态(顺序平衡)的方法，然后是已知对药物效果敏感的2小时酒精自我给药范例。我们假设，与安慰剂(0毫克/天)相比，胍法辛(1.5毫克/天或3.0毫克/天)会减少自我给药期间饮料的消耗量，而且这种影响在压力下会更明显。我们还预计，在滴定期间和与酒精联合使用期间，金刚烷将是安全和耐受性良好的，不良反应将呈剂量依赖关系。研究结果将为未来的第二阶段临床试验研究提供重要的剂量选择信息，证据表明，以去甲肾上腺素系统为靶点来降低应激反应是治疗酒精使用障碍的可行药物开发策略，并阐明了这些影响的潜在机制。

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.