TAAR1 and the Control of Wakefulness

TAAR1 和觉醒的控制

• 批准号: 8639379
• 负责人: Thomas S Kilduff
• 金额: $ 45.15万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639379
• 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; 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; public health relevance; receptor; relating to nervous system; response; sleep regulation; tool

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）：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，最近已被证明可作为微量胺相关受体1（TAAR1）的内源性配体。 TAAR1 是一种 G 蛋白偶联受体，可调节多巴胺能、血清素能以及可能的谷氨酸能活性。在最近与 F. Hoffmann-LaRoche 的科学家一起在《分子精神病学》和《生物精神病学》上发表的论文中，我们描述了新型、可穿透大脑的 TAAR1 激动剂，具有促认知、抗抑郁和抗精神病样特性，表明 TAAR1 作为治疗神经病理性疾病的新靶点。我们还表明，TAAR1 部分激动会导致觉醒程度呈剂量依赖性增加，并减少 NREM 和 REM 睡眠，表明该受体激活内源性唤醒促进系统。在本提案中，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 TAAR1 信号传导是否参与 TAAR1 缺失突变小鼠日常睡眠-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 TAAR1 激动剂的唤醒作用在这些小鼠中是否不存在。接下来，我们将确定 TAAR1 过度表达对睡眠和觉醒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 TAAR1 信号传导对于兴奋剂咖啡因和促醒治疗莫达非尼 (Provigil(R)) 以及内源性促醒神经肽下丘脑分泌素-1 (orexin-A) 的促醒作用是否是必需的。获得的结果将增进我们对 TAAR1 与大脑中觉醒促进系统相互作用的理解，并可能影响针对这一治疗睡眠/觉醒和其他神经疾病的新靶点的药物疗法的开发。