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.

抽象的 GLP-1激动剂，用于阻止可卡因欣快和自我管理可卡因成瘾仍然是当今主要的公共卫生问题，有0.3％的人口（85.5万个人）满足虐待或依赖的标准[1]。尽管有效的其他主要药物药物滥用滥用（例如酒精，选择，尼古丁），目前尚无可卡因的FDA批准药物疗法。这是确定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是肠道响应营养摄入而产生的激素的增加[2，3]。它刺激胰腺胰岛素释放并降低葡萄糖浓度[4]，这导致FDA批准GLP-1 类似于2型糖尿病（T2DM）治疗的类似物（Exendin-4或BYETTA®）。随后，临床试验表明，该药物在促进食物摄入量减少，摄入量下的其他好处高度可口的食物和体重减轻[5-7]。这些效果，以及对GLP-1中央的新兴欣赏参与大脑奖励机制促使GLP-1激动剂探索可卡因模型效果。这些研究表明，艾鉴定预处理可卡因的运动，神经化学降低（即多巴胺释放）和行为奖励的效果[3]。在当前的“概念验证”应用中，我们提出了对这些发现的临床翻译测试，探索在人类中，第一次急性（单一注射）和亚基（五日）预处理的影响胰高血糖素在主观上（例如，欣快）和行为效应等胰高血糖素（例如，自我管理）可卡因在经验丰富的，不治疗的人（n = 24）中使用A 随机，主体内安慰剂对照，交叉设计。我们假设急性和/或亚鉴定的亚慢性预处理将减少可卡因诱导的欣快感和自调节可卡因与安慰剂相比，给药（即更少的自我管理可卡因输注）。如果我们的假设是确认，这项研究将直接使用临床上适当的GLP-1激动剂进行大规模测试公式（例如，较长的表演，现在正在开发的口服代理）作为治疗的新目标可卡因依赖性。如果成功的话，当前的研究将为有望的新途径铺平道路治疗该疾病的药物开发。