TAAR1 and the Control of Wakefulness

TAAR1 和觉醒的控制

基本信息

批准号：
8900373
负责人：
Thomas S Kilduff
金额：
$ 44.84万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900373
关键词：
Adenosine Agonist Amines Amino Acids Antidepressive Agents Antipsychotic Agents Arousal Behavioral Biogenic Amines Biological Neural Networks Biological Psychiatry Brain Caffeine Cell Nucleus Central Nervous System Diseases Characteristics Cognitive Collaborations Development Disease Dose Electroencephalography G-Protein-Coupled Receptors Glutamates Health Human Ligands Maintenance Mediating Mental disorders Modafinil Molecular Monkeys Mus Mutant Strains Mice Narcolepsy Neurons Neuropeptides Neurotransmitters Normal Statistical Distribution Octopamine Paper Pattern Pharmacotherapy Phenethylamines Population Property Psychiatry Publishing REM Sleep Rattus Recruitment Activity Relative (related person)Research Rodent Role Scientist Serotonin Signal Transduction Sleep Sleep Deprivation Sleep Disorders System Testing Therapeutic Tryptamines Tyramine Wakefulness hypocretin nervous system disorder neuropsychiatry nonhuman primate novel orexin A overexpression receptor relating to nervous system response sleep regulation tool

项目摘要

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.

描述（由申请人提供）：痕量胺（TAS），内源性氨基酸代谢物先前被认为是“假神经递质”，最近已证明是痕量胺相关受体1（TAAR1）的内源配体。 TAAR1是一种G蛋白偶联受体，可调节多巴胺能，血清素能和谷氨酸能活性。在最近与F. Hoffmann-Laroche的科学家发表在分子精神病学和生物精神病学上的论文中，我们描述了具有促脑认知，抗抑郁药和抗抑制性特性的新颖，可脑渗透的TAAR1激动剂，这表明TAAR1是治疗神经病理学疾病学疾病学疾病的新型靶标。我们还表明，TAAR1局部激动剂会导致清醒的剂量依赖性增加，并减少NREM和REM睡眠，表明该受体激活了内源性唤醒系统。在本提案中，我们将确定内源性TAAR1张张张力是否有助于睡眠和清醒的正态分布，对睡眠剥夺的稳态反应以及对内源性和外源性化合物的反应已知可以促进清醒。首先，我们将确定taar1信号是否参与了每日睡眠唤醒模式的维持和TAAR1 NULL突变小鼠中睡眠的体内稳态调节。在这些研究的背景下，我们将确定这些小鼠迄今为止研究的TAAR1激动剂的唤醒作用是否不存在。接下来，我们将确定TAAR1过表达对睡眠和清醒正态分布以及对睡眠剥夺的稳态反应的后果。最后，我们将确定TAAR1信号传导是否对于刺激性咖啡因的唤醒作用以及促进唤醒的治疗莫达非尼（Provigil（r））和内源性唤醒神经肽，低载蛋白-1（orexin-a）是必需的。获得的结果将促进我们对TAAR1与大脑中唤醒性促进系统的相互作用的理解，并可能影响针对这一新型靶标治疗睡眠/唤醒和其他神经疾病的药物治疗的发展。