Schwartz Michael D, Black Sarah W, Fisher Simon P, Palmerston Jeremiah B, Morairty Stephen R, Hoener Marius C, Kilduff Thomas S
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
Neuroscience, Ophthalmology and Rare Diseases DTA, pRED, Roche Innovation Center Basel, F Hoffmann-La Roche, Basel, Switzerland.
Neuropsychopharmacology. 2017 May;42(6):1305-1314. doi: 10.1038/npp.2016.216. Epub 2016 Sep 23.
Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (T), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased T without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.
痕量胺相关受体1（TAAR1）激动剂已被证明具有促认知、抗精神病样、抗焦虑、减重、降糖和促觉醒活性。我们使用Taar1基因敲除（KO）和过表达（OE）小鼠以及TAAR1激动剂来阐明TAAR1在睡眠/觉醒中的作用。在Taar1 KO、OE和野生型（WT）小鼠中记录脑电图（EEG）、肌电图（EMG）、体温（T）和运动活动（LMA）。在进行24小时记录以表征基础睡眠/觉醒参数后，将小鼠睡眠剥夺（SD）6小时。在另一项实验中，给小鼠口服三种剂量的TAAR1部分激动剂RO5263397、咖啡因或赋形剂。与WT小鼠相比，OE小鼠的基础觉醒略有增加。在非快速眼动（NREM）和快速眼动（REM）睡眠中，与OE小鼠相比，KO小鼠的基础θ波（4.5 - 9赫兹）和低γ波（30 - 60赫兹）活动升高。睡眠剥夺后，KO和OE小鼠均表现出稳态睡眠反弹。在WT小鼠中，RO5263397增加觉醒，减少NREM和REM睡眠，在觉醒和NREM期间降低γ功率，并降低体温而不影响LMA；这些作用在KO小鼠中不存在，而在OE小鼠中增强。相比之下，与赋形剂相比，咖啡因增加了所有品系的觉醒时间、NREMγ功率和LMA；这种作用在KO小鼠中减弱，在OE小鼠中增强。TAAR1过表达适度增加觉醒，而TAAR1部分激动作用增加觉醒，同时减少NREM和REM睡眠。这些结果表明TAAR1在睡眠/觉醒和皮层活动中具有调节作用，并提示TAAR1作为促觉醒治疗的新靶点。
