Deletion of Trace Amine-Associated Receptor 1 Attenuates Behavioral Responses to Caffeine.
Deletion of Trace Amine-Associated Receptor 1 Attenuates Behavioral Responses to Caffeine.
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DOI：
10.3389/fphar.2018.00035
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发表时间：
2018
影响因子：
5.6
通讯作者：
Kilduff TS
中科院分区：
文献类型：
--
作者：
Schwartz MD;Palmerston JB;Lee DL;Hoener MC;Kilduff TS
微量胺（TAs）是内源性氨基酸代谢物，其结构与生物胺相似，是微量胺相关受体1 （TAAR1）的内源性配体，TAAR1是一种调节多巴胺能、血清素能和谷氨酸能活性的GPCR。选择性TAAR1完全和部分激动剂在啮齿类动物和非人类灵长类动物中表现出类似的促认知、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新靶点。我们之前报道过TAAR1部分激动剂在大鼠和小鼠中促进觉醒，并且TAAR1敲除（KO）和过表达的小鼠表现出睡眠-觉醒和脑电图谱组成的改变。在这里，我们报道了TAAR1 KO小鼠对精神兴奋剂莫达非尼和咖啡因的运动和脑电图谱反应减弱。TAAR1 KO小鼠和WT窝鼠分别记录脑电图和肌电图，并植入遥测发射机监测运动活动（LMA）和核心体温（Tb）。恢复后，小鼠在ZT6按平衡顺序给予莫达非尼（25、50、100 mg/kg）、咖啡因（2.5、10、20 mg/kg）或载药p.o.。在WT小鼠中，莫达非尼和咖啡因在给药后6小时内均呈剂量依赖性地增加LMA，而在KO小鼠中，每种药物只有最高剂量增加LMA，并且在给药后持续时间较短。在咖啡因的作用下，这种效应尤其明显，因此，与WT相比，在所有剂量的咖啡因下，KO小鼠的总LMA反应都显着减弱，与对照组没有差异。结核在两种基因型中均以剂量依赖的方式增加。TAAR1缺失与两种药物后的清醒巩固减少有关，但KO和WT小鼠的清醒总时间没有差异。此外，与WT小鼠相比，莫达非尼和咖啡因治疗后TAAR1 KO的伽马带脑电图活动减弱。我们的研究结果表明，TAAR1是与两种作用机制截然不同的广泛使用的精神兴奋剂相关的行为和皮层唤醒的关键组成部分。结合我们之前的研究结果，这些数据表明TAAR1是内源性尾流调节系统中一个以前未被识别的组成部分。
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 (Tb). 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. Tb 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.
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影响因子：
10.6
作者：
Black SW;Schwartz MD;Chen TM;Hoener MC;Kilduff TS
通讯作者：
Kilduff TS
影响因子：
3.3
作者：
Ehrlichman, R. S.;Gandal, M. J.;Siegel, S. J.
通讯作者：
Siegel, S. J.
安非他明、3,4-亚甲二氧基甲基苯丙胺、麦角酸二乙酰胺和儿茶酚胺神经递质的代谢物是大鼠微量胺受体的激动剂
影响因子：
3.6
作者：
Bunzow, JR;Sonders, MS;Grandy, DK
通讯作者：
Grandy, DK
影响因子：
25
作者：
Eban-Rothschild A;Rothschild G;Giardino WJ;Jones JR;de Lecea L
通讯作者：
de Lecea L
影响因子：
14.5
作者：
Fisher, Simon P.;Black, Sarah W.;Morairty, Stephen R.
通讯作者：
Morairty, Stephen R.