Effects of Semaglutide on Nicotine Intake and Smoking Lapse

索马鲁肽对尼古丁摄入量和戒烟的影响

• 批准号: 9928923
• 负责人: Christian S Hendershot
• 金额: $ 23.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928923
• 关键词: Agonist; Behavior; Behavioral; Behavioral Mechanisms; Characteristics; Cigarette; Consumption; Cross-Over Studies; Cues; Data; Development; Dopamine; Double-Blind Method; Drug Receptors; Drug Screening; Fenfluramine; Health; Human; Impulsivity; Intake; Investigation; Laboratories; Laboratory Study; Lead; Ligands; Measures; Mediating; Methods; Nicotine; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Placebos; Play; Pre-Clinical Model; Process; Randomized; Regulation; Relapse; Reporting; Rewards; Role; Self Administration; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2C; Smoker; Smoking; Time; Tobacco use; United States Food and Drug Administration; Weight maintenance regimen; Work; addiction; attenuation; base; behavioral response; behavioral study; cigarette smoking; clinical application; clinical translation; cost efficient; craving; design; drug development; incentive salience; indexing; interest; nicotine use; novel; phase II trial; pre-clinical; preclinical study; prevent; preventable death; primary outcome; public health priorities; receptor; reinforcer; response; serotonin receptor; side effect; smoking cessation

PROJECT SUMMARY Tobacco use remains the foremost cause of preventable deaths in the U.S. and worldwide. Advancing new smoking cessation therapies, including those with novel pharmacological targets, is a critical public health priority. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in the regulation of reward- related behavior, including drug seeking, in part reflecting its modulatory role in dopamine (DA) function. Historically, efforts to advance 5-HT drugs as addiction treatments have been complicated by the diversity of 5- HT receptor subtypes and their divergent influences on behavior, as well as unwanted side effects characteristic of non-selective 5-HT agents. However, the subsequent development of highly selective 5-HT receptor ligands has allowed for targeted investigations of 5-HT receptor subtypes in preclinical models of addiction. These studies show that targeted manipulation of the serotonin 5-HT2C receptor alters drug-related behavior; in particular, 5-HT2C receptor agonists are shown to reduce nicotine intake and reinstatement. Of the selective 5-HT2C receptor agonists, lorcaserin has the best near-term potential for repurposing as a smoking cessation therapy, having been approved by the U.S. Food and Drug Administration for weight management. Preclinical findings implicate several potential behavioral mechanisms by which 5-HT2C receptor agonists might reduce drug intake, including drug-specific processes (e.g., incentive salience of drug cues, self-administration, reinstatement) and drug-nonspecific behaviors (e.g., reductions in impulsivity). To date, potential mechanisms of 5-HT2C receptor agonists have not been characterized in human studies of addiction. Given emerging interest in lorcaserin as a novel smoking cessation therapy, further studies are needed to evaluate its efficacy profile, including studies to evaluate candidate treatment mechanisms. Human laboratory studies play a pivotal role in drug development by providing a time- and cost-efficient means of validating preclinical findings, also providing an ideal platform for studying mechanisms of pharmacotherapy effects. This application proposes the first targeted human laboratory investigation of lorcaserin in smokers. The effects of lorcaserin vs. placebo on smoking-related outcomes will be evaluated in a double-blind, within-subjects, crossover study with human laboratory endpoints. We also propose the first human investigation of impulsivity subdomains as candidate mechanisms for 5-HT2C receptor agonists. By evaluating an approved 5-HT2C agonist with emergent efficacy for smoking cessation, this project has near-term potential to inform clinical applications of 5-HT2C agonists for addiction.

项目概要 烟草使用仍然是美国和全世界可预防死亡的首要原因。推进新 戒烟疗法，包括具有新药理学靶点的戒烟疗法，是一项重要的公共卫生问题 优先事项。血清素（5-羟色胺；5-HT）系统广泛涉及奖赏调节 相关行为，包括寻求药物，部分反映了其对多巴胺（DA）功能的调节作用。 从历史上看，推进 5-HT 药物作为成瘾治疗的努力因 5-HT 药物的多样性而变得复杂化。 HT 受体亚型及其对行为的不同影响以及不良副作用 非选择性5-HT制剂的特征。然而，高选择性5-HT的后续发展 受体配体允许在临床前模型中对 5-HT 受体亚型进行有针对性的研究 瘾。这些研究表明，有针对性地操纵血清素 5-HT2C 受体会改变药物相关的 行为;特别是，5-HT2C 受体激动剂被证明可以减少尼古丁的摄入和恢复。的 选择性 5-HT2C 受体激动剂，氯卡色林近期最有可能重新用作吸烟药物 戒烟疗法，已获得美国食品和药物管理局批准用于体重管理。 临床前研究结果暗示了 5-HT2C 受体激动剂可能通过的几种潜在行为机制 减少药物摄入量，包括药物特异性过程（例如，药物线索的激励显着性、自我给药、 恢复）和药物非特异性行为（例如冲动性的减少）。迄今为止，潜在的机制 5-HT2C 受体激动剂的作用尚未在人类成瘾研究中得到表征。鉴于新兴 人们对氯卡色林作为一种新型戒烟疗法感兴趣，需要进一步研究来评估其疗效 概况，包括评估候选治疗机制的研究。人体实验室研究发挥着关键作用 通过提供一种时间和成本有效的方法来验证临床前研究结果，从而在药物开发中发挥作用， 为研究药物治疗作用机制提供了理想的平台。本申请提出 首次对吸烟者中的氯卡色林进行有针对性的人体实验室研究。氯卡色林与安慰剂的影响 与吸烟相关的结果将通过一项双盲、受试者内、与人类的交叉研究进行评估 实验室终点。我们还提议对冲动子域进行首次人类研究作为候选 5-HT2C 受体激动剂的作用机制。通过评估已批准的 5-HT2C 激动剂的紧急疗效 对于戒烟，该项目近期有可能为 5-HT2C 激动剂的临床应用提供信息 瘾。