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

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（Li, 2006）。鉴于有强有力的证据表明尼古丁乙酰胆碱受体（nAChR）系统参与调节酒精的作用和消耗，该系统有望成为酒精使用障碍药物开发的可行靶点。由于缺乏适合人类给药的特异性nAChR制剂，该领域的先前工作受到限制。最近FDA批准了varenicline（一种部分尼古丁激动剂），这为我们进一步了解nachr在人类饮酒中的作用提供了一个令人兴奋的机会，并评估是否应该进行临床试验调查，以检查varenicline对酒精使用障碍的疗效。对这个项目的支持来自于我们小组进行的一项试点调查（见C.1.1节）。使用已建立的酒精自我给药范式（O'Malley等人，2002），该范式对药物对酒精消耗的影响很敏感，我们评估了伐尼克兰（2mg /天）是否会改变对固定低剂量酒精的反应性。3克/分升启动饮料)和随后的随意消费大量饮酒的吸烟者和非吸烟者。Varenicline减轻了对酒精的渴望和主观酒精效应（如主观中毒），大大减少了酒精的自我给药，并且在大量饮酒的吸烟者和非吸烟者中具有良好的耐受性。这些结果反映了临床前研究伐尼克兰对乙醇寻求和消费的影响（Steensland等，2007年）。在此初步调查的基础上，我们当前应用的主要目标是对伐尼克兰进行剂量范围研究，以确定哪些剂量的伐尼克兰对减少酒精自我给药行为有效，并且安全且耐受性良好。具体来说，符合酒精使用障碍标准的吸烟者和非吸烟者将被随机分配到伐尼克兰（0、1.0、2.0 mg/天），在9天的过程中滴定到稳定状态水平，参与我们的酒精自我给药实验室范例，然后在停药后2周进行评估。我们假设，与安慰剂（0毫克/天）相比，伐尼克兰（1.0、2.0毫克/天）会减少自我给药期间的饮酒量，其次，会降低对初始酒精启动剂量的主观反应性（例如，酒精渴望）。我们还期望伐尼克兰在滴定期间和与酒精联合使用时，无论是吸烟者还是符合酒精使用障碍标准的非吸烟者，都是安全且耐受性良好的。据我们所知，这将是首次对伐尼克兰对人类饮酒影响的剂量范围调查。结果将为未来的临床试验研究提供剂量选择的重要信息，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 (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.