TAAR1 and the Control of Wakefulness

描述(申请人提供)：微量胺(TA)，以前被认为是“假神经递质”的内源性氨基酸代谢物，最近被证明是痕量胺相关受体1(TAAR1)的内源性配体。TAAR1是一种G蛋白偶联受体，调节多巴胺、5-羟色胺能，可能还有谷氨酸能活动。在最近发表在《分子精神病学和生物精神病学》上的论文中，我们与F.Hoffmann-LaRoche的科学家一起描述了具有促进认知、抗抑郁和抗精神病样属性的新型脑穿透性TAAR1激动剂，表明TAAR1是治疗神经病理疾病的新靶点。我们还表明，TAAR1部分激动剂引起剂量依赖性的觉醒增加，而NREM和REM睡眠减少，这表明该受体激活了内源性觉醒促进系统。在目前的提案中，我们将确定内源性TAAR1音调是否有助于睡眠和觉醒的正常分布，对睡眠剥夺的动态平衡反应，以及对已知促进觉醒的内源性和外源性化合物的反应。首先，我们将确定TAAR1信号是否参与了TAAR1缺失突变小鼠日常睡眠-觉醒模式的维持和睡眠的动态平衡调节。在这些研究的背景下，我们将确定迄今为止所研究的TAAR1激动剂是否在这些小鼠中缺乏促进觉醒的作用。接下来，我们将确定TAAR1过度表达对睡眠和觉醒的正常分布以及对睡眠剥夺的动态平衡反应的影响。最后，我们将确定TAAR1信号是否对于刺激剂咖啡因、促醒治疗药物莫达非尼(Provigil(R))和内源性促醒神经肽-1下丘脑-1(oresin-A)的促醒作用是必需的。所获得的结果将促进我们对TAAR1与大脑中促进觉醒的系统相互作用的理解，并可能影响针对这一新目标的药物疗法的发展，用于治疗睡眠/觉醒和其他神经疾病。

DESCRIPTION (provided by applicant): The trace amines (TAs), endogenous amino acid metabolites previously considered "false neurotransmitters," have recently been shown to act as endogenous ligands for trace amine-associated receptor 1 (TAAR1). TAAR1 is a G protein-coupled receptor that modulates dopaminergic, serotonergic and, possibly, glutamatergic activity. In papers recently published in Molecular Psychiatry and Biological Psychiatry with scientists from F. Hoffmann-LaRoche, we describe novel, brain-penetrable TAAR1 agonists with pro-cognitive, antidepressant- and antipsychotic-like properties, suggesting TAAR1 as a novel target for the treatment of neuropathological disorders. We also show that TAAR1 partial agonism causes a dose- dependent increase in wakefulness and decreases in NREM and REM sleep, indicating that this receptor activates an endogenous wake-promoting system. In the present proposal, we will determine whether endogenous TAAR1 tone contributes to the normal distribution of sleep and wakefulness, the homeostatic response to sleep deprivation, and the response to endogenous and exogenous compounds known to promote wakefulness. First, we will determine whether TAAR1 signaling is involved in the maintenance of daily sleep- wake patterns and the homeostatic regulation of sleep in TAAR1 null mutant mice. In the context of these studies, we will determine whether the wake-promoting effects of TAAR1 agonists studied to date are absent in these mice. Next, we will determine the consequences of overexpression of TAAR1 on the normal distribution of sleep and wakefulness and the homeostatic response to sleep deprivation. Lastly, we will determine whether TAAR1 signaling is necessary for the wake-promoting effects of the stimulant caffeine and the wake- promoting therapeutic modafinil (Provigil(R)) and the endogenous wake-promoting neuropeptide, hypocretin-1 (orexin-A). The results obtained will advance our understanding of the interaction of TAAR1 with wakefulness- promoting systems in the brain, and will likely impact the development of pharmacotherapies directed toward this novel target for the treatment of sleep/wake and other neural disorders.