TAAR1 agonists for nicotine addiction

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，我们的初步数据表明，急性TAAR 1激动剂治疗能够 减少尼古丁的一些成瘾作用。本申请的目的是系统地 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： 目的1将检查重复的TAAR 1激动剂（完全激动剂R0 5166017和部分激动剂R0 5166017）的作用。 RO5263397）使用短时间（1小时）尼古丁自我给药对尼古丁强化的治疗 范例;目标2将检查TAAR 1激动剂对尼古丁的恢复和孵育的影响- 具有长期（21小时）尼古丁自我给药史的大鼠的寻找行为;目标3将检查 TAAR1激动剂对长期（21小时）尼古丁自我摄取大鼠尼古丁戒断的影响， 行政史。总的来说，拟议的研究系统地评价了TAAR 1激动剂的作用， 尼古丁成瘾的四个关键方面（例如，强化效应、恢复、潜伏和消退 症状），其中每一个被认为是显着贡献尼古丁依赖和复发。成功 执行拟议的研究将证实TAAR 1在介导尼古丁成瘾中的重要作用， 提供关键的临床前证据，支持开发TAAR 1激动剂， 戒烟。

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.