TAAR 1 modulation of addiction-related effects of nicotine

TAAR 1 调节尼古丁成瘾相关效应

• 批准号: 9182100
• 负责人: Jun-Xu Li
• 金额: $ 26.7万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182100
• 关键词: Abstinence; Accounting; Agonist; Amines; Amphetamines; Attenuated; Behavior; Behavioral; Biochemical Pathway; Brain region; Bupropion; Cessation of life; Clinical; Cocaine; Cues; Data; Development; Disease; 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 Receptors; Norepinephrine; Outcome; Pharmacotherapy; Procedures; Public Health; Rattus; Reinforcement Schedule; Research; Rewards; Risk; Role; Schedule; Self Administration; Self-Administered; Sex Characteristics; Shapes; Signal Transduction; Smoker; Smoking; Stimulus; System; Testing; Therapeutic; Tobacco; Tobacco Dependence; Tobacco smoking; Tobacco use; Training; addiction; base; behavioral sensitization; combat; cost effective; dopamine transporter; male; meetings; mortality; new therapeutic target; nicotine abuse; nicotine replacement; novel; overexpression; receptor; relating to nervous system; reward circuitry; sex; 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 (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（TAAR 1）已成为开发潜在药物治疗的新目标 吸毒成瘾。特别是，TAAR 1的神经元分布与奖励的许多关键区域重叠 途径和生化研究揭示了TAAR 1信号与多巴胺之间的牢固相互作用 转运蛋白和D2受体。 TAAR 1激动剂已被证明减弱了几个与成瘾有关的 可卡因和甲基苯丙胺的行为影响。但是，taar 1在 介导尼古丁成瘾。我们最近观察到选择性TAAR 1部分激动剂RO5263397， 明显减弱尼古丁引起的行为敏化和歧视性刺激作用 尼古丁。本应用的目的是检查TAAR 1是一种新药物的假设 尼古丁成瘾治疗的目标。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对尼古丁自我自我的影响 使用固定比率和渐进式增强比例的给药（AIM 1）； 2）检查 RO5166017和RO5263397对尼古丁相关的提示和尼古丁诱导的恢复的影响 扑灭尼古丁的行为（目标2）。拟议的研究共同评估了 TAAR 1激动剂对尼古丁与成瘾相关（例如增强和恢复）作用的影响。 这些数据将提供有关TAAR 1在介导尼古丁成瘾中的作用的宝贵信息。此外， 在拟议的调查中获得的数据可能有助于识别基于新的TAAR 1 戒烟的药物治疗。