TAAR 1 modulation of addiction-related effects of nicotine

摘要 吸烟仍然是全球主要的公共卫生问题。尽管有FDA批准的 现有的治疗方案，它们远远不足以维持大多数人的长期戒烟 吸烟者。因此，发现新的有效的药物疗法来帮助戒烟仍然是一个 急切的临床需要。尼古丁是烟草中导致烟瘾的主要成分， 通过激活烟碱型乙酰胆碱受体(NAChRs)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varenicline的临床成功有限 通过直接调节中枢nAChRs。非多巴胺能系统对多巴胺能系统的间接调节 这一机制也可能能够调节尼古丁成瘾的相关效应。相关的痕量胺 受体1(Taar1)已成为潜在药物治疗的新靶点。 吸毒成瘾。特别是，TAAR 1的神经元分布与奖赏的许多关键区域重叠 途径和生化研究表明TAAR-1信号和多巴胺之间有很强的相互作用 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有关的疾病 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 调节尼古丁成瘾。我们最近观察到一种选择性的TAAR 1部分激动剂RO5263397， 显著减弱尼古丁诱导的行为敏感化和对烟碱的辨别刺激效应 尼古丁。本申请的目的是检验TAAR-1是一种新药的假设 尼古丁成瘾治疗的靶点。这一假设将通过追求两个具体目标来检验：1) 检测TAAR-1全激动剂RO5166017和部分激动剂RO5263397对尼古丁自身的影响 使用固定比率和累进比率增强表进行管理(目标1)；2)检查 RO5166017和RO5263397对尼古丁相关线索和尼古丁原诱导的恢复的影响 消除尼古丁寻觅行为(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)效应的影响。 这些数据将为TAAR1在调节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鉴定新的基于TAAR 1的 戒烟的药物疗法。

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.