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

项目总结/摘要 可卡因（COC）使用障碍（CUD）仍然是一个重要的医疗，社会和法律的公共卫生问题。 由于单独的行为疗法疗效有限， 治疗结果是迫切需要的。新出现的临床前证据支持 刺激胰高血糖素样肽1（GLP-1）受体（GLP-1 R）用于治疗CUD。临床前研究表明 GLP-1 R激动剂给药减弱COC自身给药以及COC诱导的运动 刺激4、条件性位置偏爱和丘脑核多巴胺释放。值得注意的是， 在COC自我给药后禁欲期间给予GLP-1 R激动剂可减弱 在不影响食物摄入或产生其他不良反应的剂量下恢复药物寻求行为。 尽管临床前研究结果很有希望，但COC给药可显著降低血清浓度， 由于GLP-1在人体中的作用，只有一项人体实验室研究表明GLP-1 R的给药 激动剂艾塞那肽没有改变CUD患者COC的自我给药或主观效应。 多种研究局限性，包括使用急性剂量的艾塞那肽而不是慢性预治疗， 仅评价单剂量COC，以及缺乏安慰剂COC剂量和COC替代品 (i.e.,在自由进入自我管理范式中， 艾塞那肽治疗慢性溃疡性结肠炎疗效观察。本申请的总体目的是确定GLP-1 R激动作用是否是 可行的治疗策略。这一目标将通过进行严格的人类临床试验来实现。 一项药理学研究，其中非寻求治疗的COC使用者（n=44）将被随机（1：1）分配至 维持剂量（0 mg（即，安慰剂）或每周一次皮下注射2 mg）的缓释（XR）艾塞那肽 六个星期6周的维持期，足以达到稳态，将导致更稳定 在评估治疗效果之前，测定临床有效剂量的浓度。6周前和6周后 在维持期，我们将确定COC（0、20、40 mg：IV）自我给药率。准确预测 临床疗效，我们将使用强制选择程序，参与者选择自我管理COC 或者收钱我们的中心假设是，与对照组相比，XR-exengland将减少COC自我给药。 安慰剂我们希望通过（1）使用严格的人体实验室实验设计，（2）测试治疗 达到稳态水平后的效果，以及（3）采用适当的终点来证明治疗 在实验室环境中的有效性，该项目将提供有关exenetamine潜力的明确数据 减少COC自我给药。GLP-1 R代表了与既往治疗的实质性偏离 CUD的目标，以及药物相互作用的安全性数据将为开展II期研究提供动力。 临床试验通过重新利用FDA批准的药物，没有滥用的可能性， 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.