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。虽然有FDA批准的 尽管有治疗选择，但它们远远不足以维持大多数人的长期戒烟。 吸烟者。因此，发现新的有效的药物疗法来帮助戒烟仍然是一个挑战。 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部分激动剂伐伦克林取得了有限的临床成功 通过直接调节中枢nAChRs非多巴胺能神经元对多巴胺能系统的间接调节 这种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靶点， 毒瘾特别是，TAAR 1的神经元分布与奖赏的许多关键区域重叠。 途径和生物化学研究揭示了TAAR 1信号传导和多巴胺之间的强大相互作用 转运蛋白和D2受体。TAAR 1激动剂已显示可减弱几种成瘾相关的神经递质。 可卡因和冰毒的行为影响然而，TAAR 1的作用尚不清楚， 调节尼古丁成瘾。我们最近观察到一种选择性TAAR 1部分激动剂，RO 5263397， 显著减弱尼古丁诱导的行为敏化和 尼古丁。本申请的目的是检验TAAR 1是新型药物的假设 治疗尼古丁成瘾的目标。这一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R 0 5166017和部分激动剂R 0 5263397对尼古丁自身代谢的影响。 使用固定比率和渐进比率强化计划（目标1）; 2）检查 RO 5166017和RO 5263397对尼古丁相关线索和尼古丁引发诱导的恢复的影响 尼古丁寻求行为消失（目标2）。总的来说，拟议的研究系统地评价了 TAAR 1激动剂对成瘾相关的（例如，增强和恢复）尼古丁的作用。 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，本发明还提供了一种方法， 在拟议的调查中获得的数据可能有助于识别新的TAAR 1为基础的 戒烟的药物治疗。

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.