GLP-1 Agonism for Blocking Cocaine Euphoria and Self-Administration

摘要 抑制可卡因兴奋和自我给药的GLP-1激动剂 今天，可卡因成瘾仍然是一个主要的公共卫生问题，有0.3%的人口(855,000人 个人)符合虐待或依赖的标准[1]。尽管有其他主要药物的有效药物 关于滥用药物(如酒精、鸦片、尼古丁)，目前尚无FDA批准的可卡因药物疗法。 因此，确定治疗可卡因使用障碍的有效药物是一个主要的公共卫生优先事项。 GLP-1是肠道在摄取营养物质时产生的一种胰岛素激素[2，3]。它刺激了 胰腺释放胰岛素和降低葡萄糖浓度[4]，这导致FDA批准了GLP-1 治疗2型糖尿病的类似物埃塞那肽(exendin-4或BYETA®)。后来， 临床试验证明，该药物在促进食物摄入量减少、减少摄入量方面有其他好处 非常美味的食物和减肥[5-7]。这些影响，加上对普洛斯-1的新兴欣赏-S中央 参与脑奖励机制促使在可卡因模型中探索GLP-1激动剂 效果。这些研究表明，艾塞那肽的预治疗减少了可卡因的运动，神经化学 (即，多巴胺释放)和行为奖赏效应[3]。 在目前的“概念验证”应用中，我们建议对这些发现进行临床-翻译测试，探索 首次在人类中发现急性(单次注射)和亚慢性(5天)预治疗的效果 胰高血糖素样肽-1(GLP-1)激动剂埃塞那肽对主观(如快感)和行为的影响 有经验的、未寻求治疗的吸毒者(N=24)使用A 随机、受试者内、安慰剂对照、交叉设计。我们假设急性和/或 亚慢性预用艾塞那肽可减少可卡因诱导的快感和自律可卡因 与安慰剂相比，给药(即自己注射可卡因的次数更少)。如果我们的假设是 经证实，这项研究将直接导致使用临床合适的GLP-1激动剂进行更大规模的试验 作为新的治疗目标的制剂(例如，目前正在开发中的长效口服制剂) 可卡因依赖。因此，如果成功，目前的研究将为#年有希望的新途径铺平道路。 治疗这种疾病的药物开发。

Abstract GLP-1 Agonism for Blocking Cocaine Euphoria and Self-Administration Cocaine addiction remains a major public health problem today, with 0.3% of the population (855,000 individuals) meeting criteria for abuse or dependence [1] . Despite effective medications for other major drugs of abuse (e.g., alcohol, opiates, nicotine), there is currently no FDA-approved pharmacotherapy for cocaine. Thus, identifying an effective medication for cocaine use disorders is a major public health priority. GLP -1 is an incretin hormone produced by the gut in response to nutrient ingestion [2, 3]. It stimulates pancreatic insulin release and decreases glucose concentrations [4], which led to FDA approval of the GLP-1 analog exenatide (exendin-4 or Byetta®) for the treatment of Type 2 Diabetes Mellitus (T2DM). Subsequently, clinical trials demonstrated additional benefits of the drug in promoting decreased food intake, decreased intake of highly palatable food, and weight loss [5-7]. These effects, plus an emerging appreciation of GLP-1's central involvement in brain reward mechanisms motivated the exploration of GLP-1 agonists in models of cocaine effects. These studies showed that pre-treatment with exenatide reduced cocaine's locomotor, neurochemical (i.e., dopamine releasing), and behaviorally rewarding effects [3]. In the current “proof-of-concept” application, we propose a clinical-translational test of these findings, exploring for the first time in humans the effects of acute (single injection) and subchronic (five-days) pre-treatment with the glucagon like peptide-1 (GLP-1) agonist exenatide on the subjective (e.g., euphoric) and behavioral effects (e.g., self-administration) of cocaine in experienced, non-treatment seeking users of the drug (N=24) using a randomized, within-subject, placebo-controlled, cross-over design. We hypothesize that acute and/or subchronic pretreatment with exenatide will reduce cocaine-induced euphoria and self-regulated cocaine administration (i.e., fewer self-administered cocaine infusions) as compared to placebo. If our hypothesis is confirmed, this study would lead directly to larger scale tests using clinically appropriate GLP-1 agonist formulations (e.g., longer acting, orally available agents now in development) as a new target for treating cocaine dependence. Thus, if successful, the current study will pave the way for a promising new avenue in medications development for treating the disorder.