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

GLP-1 激动剂可阻断可卡因欣快感和自我给药

基本信息

批准号：
9325489
负责人：
GUSTAVO Adolfo ANGARITA
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325489
关键词：
Acute Address Agonist Alcohols Animals Appetite Regulation Basic Science Behavior Behavioral Blood - brain barrier anatomy Body Weight decreased Brain Brain region Cell Nucleus Cells Clinical Clinical Trials Cocaine Cocaine Dependence Cocaine Users Consummatory Behavior Crossover Design Dependence Desire for food Development Diabetes Mellitus Disease Dopamine Drug user Eating Endocrinology Energy Intake Euphoria Eye FDA approved FOS gene Feeling Food Food Intake Regulation Formulation Future GLP-I receptor Glucose Glycosylated hemoglobin A Hemoglobin Human Hypothalamic structure Individual Infusion procedures Ingestion Injection of therapeutic agent Insulin Intake Investigation Laboratories Laboratory Study Lead Modeling Motor Activity Nerve Neurobiology Neurons Nicotine Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Nutrient Obesity Opiates Oral Palate Pancreas Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Phenotype Placebo Control Placebos Population Psychiatry Public Health Randomized Reporting Rewards Rodent Model Satiation Self Administration Self-Administered Testing Time Ventral Tegmental Area Work addiction analog base cocaine use drug of abuse exenatide experience fasting plasma glucose glucagon-like peptide 1 human subject incretin hormone meetings multidisciplinary neurochemistry novel therapeutic intervention peptide hormone pre-clinical pre-clinical research preference public health priorities response translational scientist

项目摘要

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.

摘要 GLP-1激动剂用于阻断可卡因欣快症和自我给药可卡因成瘾仍然是当今一个主要的公共卫生问题，有0.3%的人口（855，000人）符合滥用或依赖标准的个人）[1]。尽管其他主要药物的有效药物滥用（例如，酒精、鸦片制剂、尼古丁），但目前没有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项主要的公共卫生优先事项。 GLP-1是一种肠促胰岛素激素，由肠道响应营养摄入而产生[2，3]。它刺激胰腺胰岛素释放和降低葡萄糖浓度[4]，这导致FDA批准GLP-1 用于治疗2型糖尿病（T2 DM）的类似艾塞那肽（exendin-4或Byetta®）。随后，委员会注意到，临床试验证明了药物在促进减少食物摄入，减少摄入量， [05 - 17]饮食的营养与饮食的营养这些作用，加上GLP-1的中枢神经系统功能的新认识，参与大脑奖赏机制促使在可卡因模型中探索GLP-1激动剂方面的影响.这些研究表明，预先用exenlavine治疗，减少可卡因的运动，神经化学 (i.e.,多巴胺释放）和行为奖励效应[3]。在当前的“概念验证”应用中，我们提出了这些发现的临床转化测试，探索首次在人类中观察到急性（单次注射）和亚慢性（5天）预处理的影响，胰高血糖素样肽-1（GLP-1）激动剂对受试者（例如，欣快）和行为效应 (e.g.,自我给药）的可卡因经验丰富，非寻求治疗的药物使用者（N=24），使用随机化、受试者内、安慰剂对照、交叉设计。我们假设急性和/或用艾塞那肽亚慢性预处理将减少可卡因诱导的欣快感和自我调节的可卡因给药（即，与安慰剂相比，更少的自我施用可卡因输注）。如果我们假设经证实，本研究将直接导致使用临床适当的GLP-1激动剂进行更大规模的试验制剂（例如，目前正在开发的长效口服药物）作为治疗的新靶点可卡因依赖因此，如果成功的话，目前的研究将为一个有希望的新途径铺平道路，治疗疾病的药物开发。