A Human Laboratory Study of Exenatide for Reducing the Reinforcing Effects of Cocaine

项目摘要/摘要 可卡因(COC)使用障碍(CUD)仍然是一个重大的医疗、社会和法律公共卫生问题。 由于仅有行为疗法的疗效有限，因此确定药物疗法可以改善CUD 迫切需要治疗结果。不断涌现的临床前证据支持这一潜在的临床应用 刺激高血糖素样多肽-1受体(GLP-1R)治疗CUD。临床前研究表明 给予GLP-1R激动剂可减弱COC自身给药以及COC诱导的运动 刺激4、条件性位置偏爱和伏隔核多巴胺释放。值得注意的是， 在COC自我给药后戒断期间给予GLP-1R激动剂可减弱 在不影响食物摄入量或产生其他不良影响的剂量下恢复寻药行为。 尽管临床前发现前景看好，但服用COC显著降低了血清浓度 在人类的GLP-1中，只有一项人体实验室研究表明GLP-1R的使用 激动剂埃塞那肽并不改变慢性阻塞性肺疾病患者的自我给药或COC的主观效应。 多项研究的局限性，包括使用急性剂量的埃塞那肽，而不是慢性的预治疗， 仅评估单一剂量的COC，以及缺乏安慰剂COC剂量和替代COC的情况 (即，一种选择)在自由进入的自治范例中排除了关于 艾塞那肽治疗慢性阻塞性肺疾病的疗效。该应用的总体目标是确定GLP-1R激动剂是否是一种 CUD的可行治疗策略。这一目标将通过进行严格的人类临床试验来实现 非寻求治疗的COC使用者(n=44)将被随机(1：1)分配到 维持量(0毫克(即安慰剂)或2毫克皮下注射，每周一次)缓释(XR)艾塞那肽 六个星期。6周的维修期，足以达到稳定状态，将导致更稳定的 在评估治疗效果前的临床有效剂量浓度。在6周之前和之后 在维持期内，我们将确定COC(0，20，40 mg：IV)的自给药率。准确预测 临床疗效，我们将使用强制选择程序，参与者选择自我给药COC 或者拿到钱。我们的中心假设是XR-exenatide将减少COC自我给药。 安慰剂。我们期望通过(1)使用严格的人体实验室实验设计，(2)测试治疗 达到稳定水平后的影响，以及(3)采用适当的终点来演示治疗 在实验室环境下的有效性，该项目将提供有关埃塞那肽潜力的明确数据。 用于减少COC的自我管理。GLP-1R代表着与以前的治疗有很大的不同 CUD的目标和药物-药物相互作用的安全性数据将为进行第二阶段提供动力 临床试验。通过改变FDA批准的不具有滥用潜力的药物的用途，艾塞那肽可以 通过开发管道推进，从而更快地影响临床研究和实践。

PROJECT SUMMARY/ABSTRACT Cocaine (COC) use disorder (CUD) remains a significant medical, social, and legal public-health concern. Because behavioral therapies alone have limited efficacy, identification of pharmacotherapy that improves CUD treatment outcomes is sorely needed. Emerging preclinical evidence supports the potential clinical utility of stimulating the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) for treating CUD. Preclinical studies show that administration of a GLP-1R agonist attenuates COC self-administration, as well as COC-induced locomotor stimulation4, conditioned place preference, and dopamine release in the nucleus accumbens. Significantly, administering a GLP-1R agonist during abstinence following COC self-administration attenuated the reinstatement of drug-seeking behavior at doses that did not affect food intake or produce other adverse effects. Despite promising preclinical findings, and that COC administration significantly reduces serum concentrations of GLP-1 in humans, there has been only one human laboratory study in which administration of the GLP-1R agonist, exenatide, did not alter either the self-administration or subjective effects of COC in people with CUD. Multiple study limitations, including the use of an acute dose of exenatide rather than chronic pre-treatment, evaluation of only a single dose of COC, as well as the lack of both a placebo COC dose and an alternative to COC (i.e., a choice) in the free-access self-administration paradigm preclude drawing firm conclusions about the efficacy of exenatide for CUD. The overall objective of this application is to determine if GLP-1R agonism is a viable treatment strategy for CUD. This goal will be achieved through the conduct of a rigorous human clinical pharmacology study in which non-treatment seeking COC users (n=44) will be randomized (1:1) to a maintenance dose (0 mg (i.e., placebo) or 2 mg subcutaneously once a week) of extended-release (XR) exenatide for six weeks. The 6-week maintenance period, sufficient to achieve steady-state, will result in more stable concentrations of clinically effective doses before assessing treatment effects. Before and after the 6-week maintenance period, we will determine COC (0, 20, 40 mg: IV) self-administration rates. To accurately predict clinical efficacy, we will use forced-choice procedures in which participants choose to either self-administer COC or receive money. Our central hypothesis is that XR-exenatide will reduce COC self-administration compared to placebo. We expect that by (1) using a rigorous human laboratory experimental design, (2) testing treatment effects after achieving steady-state levels, and (3) employing appropriate endpoints for demonstrating treatment effectiveness in a laboratory setting, this project will provide definitive data regarding the potential of exenatide for reducing COC self-administration. The GLP-1R represents a substantial departure from previous treatment targets for CUD, and the drug-drug interaction safety data will provide the impetus for conducting a Phase II clinical trial. By repurposing an FDA-approved medication that does not have abuse potential, exenatide can advance through the development pipeline, thereby impacting clinical research and practice more quickly.