TAAR1 and the Control of Wakefulness

描述（由申请人提供）：痕量胺（TA），以前被认为是“假神经递质”的内源性氨基酸代谢物，最近已被证明可作为痕量胺相关受体1（TAAR 1）的内源性配体。TAAR 1是一种G蛋白偶联受体，可调节多巴胺能、多巴胺能和可能的多巴胺能活性。在最近发表在《分子精神病学》和《生物精神病学》上的论文中，来自F。Hoffmann-LaRoche，我们描述了一种新型的、脑可穿透的TAAR 1激动剂，具有促认知、抗抑郁和抗精神病样特性，表明TAAR 1是治疗神经病理性疾病的新靶点。我们还表明，TAAR 1部分激动剂引起剂量依赖性觉醒增加和NREM和REM睡眠减少，表明该受体激活内源性促醒系统。在本提案中，我们将确定内源性TAAR 1音调是否有助于睡眠和觉醒的正常分布，对睡眠剥夺的稳态反应，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TAAR 1信号转导是否参与TAAR 1无效突变小鼠日常睡眠-觉醒模式的维持和睡眠的稳态调节。在这些研究的背景下，我们将确定迄今为止研究的TAAR 1激动剂的促醒作用是否在这些小鼠中不存在。接下来，我们将确定TAAR 1过表达对睡眠和觉醒的正常分布以及对睡眠剥夺的稳态反应的影响。最后，我们将确定TAAR 1信号传导是否是刺激性咖啡因和促醒治疗性莫达非尼（Provigil（R））以及内源性促醒神经肽下丘脑泌素-1（食欲素-A）的促醒作用所必需的。所获得的结果将促进我们对TAAR 1与大脑中的觉醒促进系统的相互作用的理解，并且将可能影响针对用于治疗睡眠/觉醒和其他神经障碍的这种新靶点的药物疗法的开发。

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.