Dose ranging study of varenicline on human alcohol self-administration behavior

说明(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(Li，2006)。鉴于有强有力的证据表明烟碱型乙酰胆碱受体(NAChR)系统参与调节酒精的效应和消费，该系统有望成为治疗酒精使用障碍的药物开发的可行靶点。由于缺乏用于人类管理的合适和特定的nAChR试剂，这一领域的先前工作一直受到限制。FDA最近批准了部分尼古丁激动剂varenicline，这为我们提供了一个令人兴奋的机会，以进一步了解nAChRs在人类酒精消费中的作用，并评估是否应该继续进行临床试验调查，检查varenicline对酒精使用障碍的疗效。对该项目的支持来自我们小组进行的一项试点调查(见第C.1.1节)。使用对药物对酒精消费的影响敏感的已建立的酒精自我给药范例(O‘Malley等人，2002年)，我们评估了varenicline(每天2毫克)是否改变了重度饮酒吸烟者和不吸烟者对固定低剂量酒精(0.03g/dl启动饮料)的反应性以及随后的即兴饮酒。作为对启动饮料的反应，varenicline减轻了对酒精的渴望和主观酒精效应(例如，主观醉酒)，有力地减少了酒精自我给药，并且在酗酒吸烟者和不吸烟者中耐受性良好。这些结果反映了检验varenicline对乙醇寻求和消费的影响的临床前研究(Steensland等人，2007年)。在这项初步研究的基础上，我们目前应用的主要目标是进行varenicline的剂量范围研究，以确定哪些剂量的varenicline对减少酒精自我给药行为有效，并且是安全和耐受性良好的。具体地说，符合酒精使用障碍标准的吸烟者和非吸烟者将被随机服用varenicline(0，1.0，2.0 mg/天)，在9天的过程中滴定到稳定水平，参加我们的酒精自我给药实验室范例，然后在停药后进行2周的评估。我们假设，与安慰剂(0毫克/天)相比，瓦伦尼克林(1.0，2.0毫克/天)将减少自我给药期间饮料的消耗量，其次，将减少对初始酒精启动剂量的主观反应性(例如，酒精渴望)。我们还预计，在滴定期间，在吸烟者和符合酒精使用障碍标准的非吸烟者中，varenicline将是安全和耐受性良好的。据我们所知，这将是第一次对伐伦克林对人类酒精消费的影响进行剂量范围的调查。研究结果将为未来的临床试验研究提供重要的剂量选择信息，证明尼古丁系统是治疗酒精使用障碍的可行药物靶点，并阐明这些影响的潜在机制。 公共卫生相关性：鉴于有强有力的证据表明烟碱型乙酰胆碱受体(NAChR)系统参与调节酒精的影响和消费，该系统有望成为酒精使用障碍药物开发的可行靶点。FDA最近批准了部分尼古丁激动剂varenicline，这为我们提供了一个令人兴奋的机会，以进一步了解nAChRs在人类酒精消费中的作用，并评估是否应该继续进行临床试验调查，检查varenicline对酒精使用障碍的疗效。使用实验室范例，我们目前应用的主要目标是进行varenicline的剂量范围研究，以确定哪些剂量的varenicline对减少酒精自我给药行为有效，并且对符合酒精使用障碍标准的吸烟者和非吸烟者是安全和耐受性良好的。

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 (Li , 2006). Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. Prior work in this area has been limited due to the lack of suitable and specific nAChR agents for human administration. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Support for this project comes from a pilot investigation conducted by our group (see Section C.1.1). Using an established alcohol self-administration paradigm (O'Malley et al., 2002) that is sensitive to medication effects on alcohol consumption, we evaluated whether varenicline (2 mg/day) altered reactivity to a fixed low dose of alcohol (.03 g/dl priming drink) and subsequent ad-libitum consumption in heavy drinking smokers and non-smokers. Varenicline attenuated alcohol craving and subjective alcohol effects (e.g., subjective intoxication) in response to the priming drink, robustly reduced alcohol self-administration, and was well tolerated in heavy drinking smokers and non-smokers. These results mirror preclinical studies examining the effect of varenicline on ethanol seeking and consumption (Steensland et al., 2007). Building on this preliminary investigation, our primary goal in the current application is to conduct a dose ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self- administration behavior, and are safe and well tolerated. Specifically, smokers and non-smokers who meet criteria for alcohol use disorders will be randomized to varenicline (0, 1.0, 2.0 mg/day), titrated to steady state levels over the course of 9 days, participate in our alcohol self-administration laboratory paradigm, and then assessed for 2-weeks following medication discontinuation. We hypothesize that varenicline (1.0, 2.0 mg/day) compared to placebo (0 mg/day) will decrease the number of drinks consumed during the self-administration period, and secondarily, will reduce subjective reactivity (e.g., alcohol craving) to the initial priming dose of alcohol. We also expect that varenicline will be safe and well tolerated during the titration period and in combination with alcohol in both smokers and non-smokers who meet criteria for alcohol use disorders. To our knowledge, this will be the first dose-ranging investigation of varenicline effects on human alcohol consumption. Results will provide important information concerning dose selection for future clinical trial investigations, evidence that the nicotinic system is a viable medications target for alcohol use disorders, and elucidate potential mechanisms for these effects. PUBLIC HEALTH RELEVANCE: Given the strong evidence that the nicotinic acetylcholine receptor (nAChR) system is involved in modulating alcohol effects and consumption, this system holds promise as a viable target for medications development for alcohol use disorders. The recent FDA approval of varenicline, a partial nicotinic agonist, presents an exciting opportunity to further our understanding of the role of nAChRs in human alcohol consumption, and to evaluate whether clinical trial investigations examining the efficacy of varenicline for alcohol use disorders should be pursued. Using a laboratory paradigm, our primary goal in the current application is to conduct a dose-ranging study of varenicline to determine which doses of varenicline are efficacious for reducing alcohol self-administration behavior, and are safe and well tolerated in smokers and non-smokers who meet criteria for alcohol use disorders.