Schwartz Michael D, Palmerston Jeremiah B, Lee Diana L, Hoener Marius C, Kilduff Thomas S
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, United States.
Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
Front Pharmacol. 2018 Feb 2;9:35. doi: 10.3389/fphar.2018.00035. eCollection 2018.
Trace amines (TAs), endogenous amino acid metabolites that are structurally similar to the biogenic amines, are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 full and partial agonists exhibit similar pro-cognitive, antidepressant- and antipsychotic-like properties in rodents and non-human primates, suggesting TAAR1 as a novel target for the treatment of neurological and psychiatric disorders. We previously reported that TAAR1 partial agonists are wake-promoting in rats and mice, and that TAAR1 knockout (KO) and overexpressing mice exhibit altered sleep-wake and EEG spectral composition. Here, we report that locomotor and EEG spectral responses to the psychostimulants modafinil and caffeine are attenuated in TAAR1 KO mice. TAAR1 KO mice and WT littermates were instrumented for EEG and EMG recording and implanted with telemetry transmitters for monitoring locomotor activity (LMA) and core body temperature (T). Following recovery, mice were administered modafinil (25, 50, 100 mg/kg), caffeine (2.5, 10, 20 mg/kg) or vehicle p.o. at ZT6 in balanced order. In WT mice, both modafinil and caffeine dose-dependently increased LMA for up to 6 h following dosing, whereas only the highest dose of each drug increased LMA in KO mice, and did so for less time after dosing. This effect was particularly pronounced following caffeine, such that total LMA response was significantly attenuated in KO mice compared to WT at all doses of caffeine and did not differ from Vehicle treatment. T increased comparably in both genotypes in a dose-dependent manner. TAAR1 deletion was associated with reduced wake consolidation following both drugs, but total time in wakefulness did not differ between KO and WT mice. Furthermore, gamma band EEG activity following both modafinil and caffeine treatment was attenuated in TAAR1 KO compared to WT mice. Our results show that TAAR1 is a critical component of the behavioral and cortical arousal associated with two widely used psychostimulants with very different mechanisms of action. Together with our previous findings, these data suggest that TAAR1 is a previously unrecognized component of an endogenous wake-modulating system.
痕量胺（TAs）是内源性氨基酸代谢产物，其结构与生物胺相似，是痕量胺相关受体1（TAAR1）的内源性配体，TAAR1是一种调节多巴胺能、5-羟色胺能和谷氨酸能活性的G蛋白偶联受体（GPCR）。选择性TAAR1完全激动剂和部分激动剂在啮齿动物和非人灵长类动物中表现出相似的促认知、抗抑郁和抗精神病样特性，这表明TAAR1是治疗神经和精神疾病的一个新靶点。我们之前报道过，TAAR1部分激动剂在大鼠和小鼠中具有促进觉醒的作用，并且TAAR1基因敲除（KO）和过表达小鼠的睡眠-觉醒和脑电图频谱组成发生了改变。在此，我们报道在TAAR1基因敲除小鼠中，对精神振奋剂莫达非尼和咖啡因的运动和脑电图频谱反应减弱。将TAAR1基因敲除小鼠和野生型同窝小鼠进行脑电图和肌电图记录，并植入遥测发射器以监测运动活动（LMA）和核心体温（T）。恢复后，小鼠按平衡顺序在ZT6口服给予莫达非尼（25、50、100mg/kg）、咖啡因（2.5、10、20mg/kg）或赋形剂。在野生型小鼠中，给药后长达6小时，莫达非尼和咖啡因均剂量依赖性地增加LMA，而在基因敲除小鼠中，每种药物只有最高剂量增加LMA，且给药后增加的时间较短。这种效应在咖啡因给药后尤为明显，以至于在所有咖啡因剂量下，基因敲除小鼠的总LMA反应与野生型小鼠相比均显著减弱，且与赋形剂处理组无差异。两种基因型的体温均以剂量依赖性方式相应升高。TAAR1缺失与两种药物给药后觉醒巩固的降低有关，但基因敲除小鼠和野生型小鼠的总觉醒时间没有差异。此外，与野生型小鼠相比，TAAR1基因敲除小鼠在莫达非尼和咖啡因治疗后的γ波段脑电图活动减弱。我们的结果表明，TAAR1是与两种作用机制截然不同的广泛使用的精神振奋剂相关的行为和皮层觉醒的关键组成部分。结合我们之前的研究结果，这些数据表明TAAR1是内源性觉醒调节系统中一个先前未被认识的组成部分。
