TAAR1 agonists for nicotine addiction

TAAR1 激动剂治疗尼古丁成瘾

• 批准号: 10092996
• 负责人: Jun-Xu Li
• 金额: $ 39.44万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092996
• 关键词: Abstinence; Acute; Agonist; Amines; Attenuated; Behavior; Behavioral; Bupropion; Cessation of life; Clinical; Cocaine; Cues; Data; Development; Dopamine; Dose; Drug Addiction; Extinction (Psychology); FDA approved; Female; Filament; Food; Health Care Costs; Hour; Hyperalgesia; Infusion procedures; Intravenous; Maintenance; Mecamylamine; Mechanics; Mediating; Methamphetamine; Mission; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Protocols documentation; Psychological reinforcement; Public Health; Rattus; Recording of previous events; Regimen; Research; Role; Schedule; Self Administration; Sex Differences; Smoker; Smoking; System; Testing; Therapeutic; Tobacco; Tobacco Dependence; Tobacco smoking behavior; Tobacco use; Training; United States National Institutes of Health; Withdrawal; Withdrawal Symptom; addiction; anxiety-like behavior; combat; cost effective; dependence relapse; efficacious treatment; experience; inhibitor/antagonist; male; men' s group; monoamine; mortality risk; nicotine replacement; nicotine seeking behavior; novel; pre-clinical; receptor; reuptake; smoking abstinence; smoking cessation; success; transmission process; varenicline

ABSTRACT Tobacco smoking remains a major public health concern globally. Although there are FDA-approved therapeutic options available, they are far from adequate to maintain long-term smoking abstinence in most smokers. Thus, discovering novel efficacious pharmacotherapies to aid in smoking cessation remains an urgent clinical need. Nicotine, the major component in tobacco that is responsible for tobacco addiction, stimulates the mesolimbic dopaminergic system via activating nicotinic acetylcholine receptors (nAChRs). Nicotine replacement therapy and the nAChR partial agonist varenicline have achieved limited clinical success by directly modulating the central nAChRs. Indirect modulation of dopaminergic system by non-dopaminergic mechanism may also be able to modulate the addiction-related effects of nicotine. Trace amine associated receptor 1 (TAAR1) has emerged as a novel target for the development of potential pharmacotherapy to treat drug addiction. In particular, our preliminary data have shown that acute TAAR1 agonist treatment is able to reduce some addiction-related effects of nicotine. The objective of the present application is to systematically assess the therapeutic potential of TAAR1 agonists on nicotine addiction. Three Specific Aims are proposed: Aim 1 will examine the effects of repeated TAAR1 agonists (full agonist RO5166017 and partial agonist RO5263397) treatment on nicotine reinforcement using a short-access (1 hour) nicotine self-administration paradigm; Aim 2 will examine the effects of TAAR1 agonists on the reinstatement and incubation of nicotine- seeking behavior in rats with a long-access (21 hours) nicotine self-administration history; Aim 3 will examine the effects of TAAR1 agonists on nicotine withdrawal in rats with a long-access (21 hours) nicotine self- administration history. Collectively, the proposed studies systematically evaluate the effects of TAAR1 agonists on four critical aspects of nicotine addiction (e.g., reinforcing effects, reinstatement, incubation and withdrawal symptoms), each of which is thought to contribute significantly to nicotine dependence and relapse. Successful execution of the proposed studies will confirm the essential role TAAR1 in mediating nicotine addiction and provide critical preclinical evidence in support of developing TAAR1 agonists are novel pharmacotherapy for smoking cessation.

抽象的 吸烟在全球范围内仍然是一个主要的公共健康问题。虽然有FDA批准 可用的治疗选择，它们远远不足以维持大多数的长期戒烟 吸烟者。因此，发现新颖的有效药物治疗以帮助戒烟仍然是 紧急临床需求。尼古丁，烟草中负责烟草成瘾的主要成分， 通过激活烟碱乙酰胆碱受体（NACHRS）刺激中唇多巴胺能系统。 尼古丁替代疗法和NACHR部分激动剂葡萄烯已取得有限的临床成功 通过直接调节中央NACHR。非多巴胺能对多巴胺能系统的间接调节 机制也可能能够调节尼古丁的成瘾相关作用。痕量胺相关 受体1（TAAR1）已成​​为开发潜在药物治疗的新目标 吸毒成瘾。特别是，我们的初步数据表明，急性TAAR1激动剂治疗能够 减少尼古丁的一些与成瘾相关的作用。本应用的目的是系统地 评估TAAR1激动剂对尼古丁成瘾的治疗潜力。提出了三个具体目标： AIM 1将检查重复的TAAR1激动剂的影响（完全激动剂RO5166017和部分激动剂 RO5263397）使用短期访问（1小时）尼古丁自我给药治疗尼古丁增强 范例; AIM 2将检查TAAR1激动剂对尼古丁恢复和孵育的影响 在老鼠中寻求长期访问（21小时）尼古丁自我管理史的行为； AIM 3将检查 TAAR1激动剂对长期（21小时）尼古丁自我的大鼠尼古丁戒断的影响 行政历史。总体而言，拟议的研究系统地评估了TAAR1激动剂的影响 在尼古丁成瘾的四个关键方面（例如，加强效果，恢复，孵化和戒断 症状），每种症状都对尼古丁的依赖性和复发产生了重大贡献。成功的 拟议研究的执行将确认TAAR1在介导尼古丁成瘾和 提供关键的临床前证据以支持开发TAAR1激动剂是新型药物治疗 戒烟。