The Effects of Exenatide, a GLP-1 Agonist, on Alcohol Self-Administration in Heavy Drinkers

项目摘要 在美国，超过1600万成年人患有酒精使用障碍（AUD）， 澳元的年经济负担为2490亿美元。大约有88，000名美国人死于与酒精有关的疾病。 在美国，未经治疗的AUD是第四大最可预防的死亡原因。四种药物 已经被FDA批准用于治疗AUD，但这些药物中没有一种被证明是有效的。 不同的饮酒者群体更有效地治疗成瘾是国家重要的目标， 加速AUD的药物开发是NIAAA的优先事项之一。该提案旨在回答 这就要求通过探索胰高血糖素样肽-1（GLP-1）的潜力来加速药物开发 激动剂艾塞那肽作为治疗AUD的候选药物。现在有大量的临床前 GLP-1激动剂可以减弱消费和寻求行为的证据 几种常见的滥用物质，包括酒精、可卡因和尼古丁。GLP-1激动剂Exendin-4 和利拉鲁肽已被证明可以减少啮齿动物的酒精消耗， 位置偏好用Exendin-4阻断治疗增加酒精摄入量 剥夺，表明这种药物可能会降低复发的可能性。也有证据表明 Exendin-4诱导的酒精消耗减少不会发生在缺失中枢神经系统的突变小鼠中。 神经系统GLP-1受体。尚未发表检测GLP-1激动剂作用的临床研究 酒精消费。本研究旨在通过测试一种 这是一种市售的和耐受性良好的药物，其成本仅为新药发现的一小部分。概无 FDA批准的AUD药物或适应症外AUD药物靶向这一GLP-1途径，使exenadine成为一种 用于AUD药物开发的有前景的化合物。本研究的具体目的是测试 实验1）酒精自我管理和酗酒者的渴望，2）酒精吸收，和3） 在饮酒过程中的血糖水平。5 mcg剂量艾塞那肽或假注射的效果将是 在人类实验室中使用酒精自我给药方法进行评价。在这项受试者内交叉研究中， 设计，将36名重度饮酒者随机分配至暴露顺序（exengland或假注射）， 完成两项酒精自我管理试验。受试者将接受酒精启动饮料，并将 在两小时内可以喝8杯。我们预计，受试者在接受治疗后会减少饮酒。 与接受假注射相比，给予艾塞那肽。显著艾塞那肽诱导 饮酒量的减少将被认为是这种药物可能具有作为AUD的价值的迹象 药这项研究可能为II期随机对照试验提供了依据， AUD人口。这些结果也可能有助于促进对exenetrine作用的进一步临床研究。 和其他可用的GLP-1激动剂对酒精消耗调节中涉及的因素的影响。

Project Summary More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated annual economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related causes each year; untreated AUD is the fourth most preventable cause of death in the US. Four medications have been FDA-approved for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of drinkers. Treating addiction more effectively is goal with national importance and accelerating drug development for AUD is one of the priorities for NIAAA. This proposal is intended to answer this call for accelerating drug development by exploring the potential of a glucagon-like peptide-1 (GLP-1) agonist, exenatide, as a candidate medication for the treatment of AUD. There is now substantial preclinical evidence that GLP-1 agonists can attenuate behaviors that model both the consumption and seeking of several commonly abused substances including alcohol, cocaine, and nicotine. The GLP-1 agonists Exendin-4 and liraglutide have been shown to reduce alcohol consumption by rodents and attenuate alcohol-induced place preference. Treatment with Exendin-4 blocks increases in alcohol intake following periods of alcohol deprivation, suggesting that this drug may decrease the likelihood of relapse. There is also evidence that Exendin-4 induced reductions in alcohol consumption do not occur in mutant mice who are missing central nervous system GLP-1 receptors. There are no published clinical studies testing the effects of GLP-1 agonists on alcohol consumption. This study is intended to accelerate medication development for AUD by testing a commercially-available and well-tolerated agent at a fraction of the cost of new drug discovery. None of the FDA-approved AUD medications or off-label AUD medications target this GLP-1 pathway, making exenatide a promising compound for AUD drug development. The specific aims of this study are to test the effects of exenatide on 1) alcohol self-administration and craving among heavy drinkers, 2) alcohol absorption, and 3) blood glucose levels during a drinking task. The effects of 5mcg dose of exenatide or sham injection will be evaluated in a human laboratory using an alcohol self-administration method. In this within-subjects crossover design, 36 heavy drinkers will be randomized to exposure order (exenatide or sham injection) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 drinks over a 2-hour period. We anticipate that subjects will consume less alcohol following the administration of exenatide compared to when they receive a sham injection. Significant exenatide-induced reductions in drinking will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II RCTs testing exenatide with a treatment-seeking AUD population. These results may also help to spur further clinical investigation of the effects of exenatide and other available GLP-1 agonists on the factors implicated in the regulation of alcohol consumption.