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TAAR 1 modulation of addiction-related effects of nicotine

TAAR 1 调节尼古丁成瘾相关效应

基本信息

批准号：
9307798
负责人：
Jun-Xu Li
金额：
$ 21.22万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307798
关键词：
Abstinence Agonist Amination Amines Amphetamines Attenuated Behavior Behavioral Biochemical Brain region Bupropion Cessation of life Clinical Cocaine Cues Data Development Dopamine Dopamine D2 Receptor Dopamine Uptake Inhibitors Dose Drug Addiction FDA approved Female Future Health Care Costs Intravenous Investigation Knock-out Maintenance Mediating Methamphetamine Mission Mus Neurons Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Agonists Nicotinic Receptors Norepinephrine Outcome Pathway interactions Pharmacology Pharmacotherapy Procedures Public Health Rattus Reinforcement Schedule Research Rewards Risk Role Schedule Self Administration Self-Administered Sex Characteristics Signal Transduction Smoker Smoking Stimulus System Testing Therapeutic Tobacco Tobacco Dependence Tobacco smoking Tobacco use Training United States National Institutes of Health addiction base behavioral sensitization combat cost effective dopamine transporter male mortality new therapeutic target nicotine abuse nicotine replacement novel overexpression receptor relating to nervous system reward circuitry sex smoking cessation success transmission process varenicline

项目摘要

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 (TAAR 1) has emerged as a novel target for the development of potential pharmacotherapy to treat drug addiction. In particular, the neuronal distribution of TAAR 1 overlaps with many key regions of the reward pathway, and biochemical studies reveal robust interactions between TAAR 1 signaling and dopamine transporters and D2 receptors. TAAR 1 agonists have been shown to attenuate several addiction-related behavioral effects of cocaine and methamphetamine. However, it is unknown of the role of TAAR 1 in mediating nicotine addiction. We recently observed that a selective TAAR 1 partial agonist, RO5263397, markedly attenuates nicotine induced behavioral sensitization and the discriminative stimulus effects of nicotine. The objective of the present application is to examine the hypothesis that TAAR 1 is a novel drug target for the treatment of nicotine addiction. This hypothesis will be tested by pursuing two specific aims: 1) examine the effects of TAAR 1 full agonist RO5166017 and partial agonist RO5263397 on nicotine self- administration using both fixed ratio and progressive ratio schedules of reinforcement (Aim 1); 2) examine the effects of RO5166017 and RO5263397 on nicotine-associated cue- and nicotine prime-induced reinstatement of extinguished nicotine-seeking behavior (Aim 2). Collectively, the proposed studies systematically evaluate the effects of TAAR 1 agonists on the addiction-related (e.g., reinforcing and reinstatement) effects of nicotine. These data will provide valuable information on the role of TAAR 1 in mediating nicotine addiction. In addition, data obtained in the proposed investigation may contribute to the identification of novel TAAR 1-based pharmacotherapy for smoking cessation.

抽象的吸烟仍然是全球主要的公共卫生问题。虽然有 FDA 批准的尽管有可用的治疗选择，但它们远远不足以维持大多数人的长期戒烟吸烟者。因此，发现新的有效药物疗法来帮助戒烟仍然是一个重要的任务。临床急需。尼古丁是烟草中导致烟草成瘾的主要成分，通过激活烟碱乙酰胆碱受体 (nAChR) 刺激中脑边缘多巴胺能系统。尼古丁替代疗法和 nAChR 部分激动剂伐尼克兰取得的临床成功有限通过直接调节中枢 nAChR。非多巴胺能系统间接调节多巴胺能系统该机制还可能能够调节尼古丁的成瘾相关作用。微量胺相关受体 1 (TAAR 1) 已成为开发潜在药物疗法的新靶点毒瘾。特别是，TAAR 1 的神经元分布与奖励的许多关键区域重叠通路和生化研究揭示了 TAAR 1 信号传导与多巴胺之间的强大相互作用转运蛋白和 D2 受体。 TAAR 1 激动剂已被证明可以减轻几种与成瘾相关的症状可卡因和甲基苯丙胺的行为影响。然而，目前尚不清楚 TAAR 1 在调解尼古丁成瘾。我们最近观察到选择性 TAAR 1 部分激动剂 RO5263397 显着减弱尼古丁引起的行为过敏和歧视性刺激效果尼古丁。本申请的目的是检验 TAAR 1 是一种新药的假设治疗尼古丁成瘾的目标。该假设将通过追求两个具体目标来检验：1）检查 TAAR 1 完全激动剂 RO5166017 和部分激动剂 RO5263397 对尼古丁自体的影响使用固定比例和渐进比例强化计划进行管理（目标 1）； 2）检查 RO5166017和RO5263397对尼古丁相关提示和尼古丁引发恢复的影响消除寻求尼古丁的行为（目标 2）。总的来说，拟议的研究系统地评估了 TAAR 1 激动剂对尼古丁成瘾相关（例如，增强和恢复）作用的影响。这些数据将为 TAAR 1 在介导尼古丁成瘾中的作用提供有价值的信息。此外，在拟议的调查中获得的数据可能有助于识别基于 TAAR 1 的新型药物戒烟药物治疗。