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，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（Li，2006）。鉴于强有力的证据表明，烟碱乙酰胆碱受体（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目标。由于缺乏合适的和特定的nAChR药物用于人类管理，在这方面的先前工作受到限制。最近FDA批准的varenicline，部分烟碱激动剂，提供了一个令人兴奋的机会，以进一步了解nAChRs在人类饮酒中的作用，并评估是否应继续进行检查varenicline对酒精使用障碍的疗效的临床试验研究。对本项目的支持来自我们小组进行的试点调查（见第C.1.1节）。使用已建立的酒精自我给药范例（O 'Malley等人，2002），其对药物对酒精消耗的影响敏感，我们评估了伐尼克兰（2 mg/天）是否改变了对固定低剂量酒精（0.03g/dl启动饮料）的反应性以及随后在重度饮酒的吸烟者和非吸烟者中的自由饮用。伐尼克兰减弱了酒精渴求和主观酒精效应（例如，主观中毒），强烈减少酒精自我管理，并在大量饮酒的吸烟者和非吸烟者中耐受良好。这些结果反映了检查伐尼克兰对乙醇寻求和消耗的影响的临床前研究（Steenkirk等人，2007年）。在此初步研究的基础上，我们在本申请中的主要目标是进行伐尼克兰的剂量范围研究，以确定哪些剂量的伐尼克兰对于减少酒精自我给药行为是有效的，并且是安全和良好耐受的。具体而言，符合酒精使用障碍标准的吸烟者和非吸烟者将随机接受伐尼克兰（0、1.0、2.0 mg/天）治疗，在9天内滴定至稳态水平，参与我们的酒精自我给药实验室范例，然后在停药后评估2周。我们假设伐尼克兰（1.0，2.0 mg/天）与安慰剂（0 mg/天）相比，将减少自我给药期间消耗的饮料数量，其次，将减少主观反应（例如，酒精渴望）到酒精的初始引发剂量。我们还预计，凡尼克兰在滴定期间以及与酒精联合治疗符合酒精使用障碍标准的吸烟者和非吸烟者时都是安全的，耐受性良好。据我们所知，这将是第一个剂量范围的研究伐尼克兰对人类饮酒的影响。结果将为未来的临床试验研究提供有关剂量选择的重要信息，证明尼古丁系统是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。 公共卫生相关性：鉴于强有力的证据表明，烟碱乙酰胆碱受体（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目标。最近FDA批准的varenicline，部分烟碱激动剂，提供了一个令人兴奋的机会，以进一步了解nAChRs在人类饮酒中的作用，并评估是否应继续进行检查varenicline对酒精使用障碍的疗效的临床试验研究。使用实验室范例，我们在本申请中的主要目标是进行伐尼克兰的剂量范围研究，以确定哪些剂量的伐尼克兰对于减少酒精自我给药行为是有效的，并且在满足酒精使用障碍标准的吸烟者和非吸烟者中是安全和良好耐受的。

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.