Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA 94025, USA.
Neuroscience and Rare Diseases Discovery & Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
Int J Mol Sci. 2024 Oct 22;25(21):11351. doi: 10.3390/ijms252111351.
Trace amine-associated receptor 1 (TAAR1) is a negative regulator of dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in rodents and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake regulation were due, in part, to DA release. Male C57BL6/J mice ( = 8) were intraperitoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combination of D1R + D2R antagonists, or saline at ZT5.5, followed 30 min later by RO5263397 or vehicle per os. EEG, EMG, subcutaneous temperature, and activity were recorded across the 8 treatments and sleep architecture was analyzed for 6 h post-dosing. As described previously, RO5263397 increased wakefulness and delayed NREM and REM sleep onset. D1, D2, and D1 + D2 pretreatment reduced RO5263397-induced wakefulness for 1-2 h after dosing but only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected the TAAR1-mediated suppression of REM sleep. These results suggest that, whereas the TAAR1 effects on wakefulness are mediated, in part, through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. In contrast, the TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms.
痕量胺相关受体 1（TAAR1）是多巴胺（DA）释放的负调节剂。部分 TAAR1 激动剂 RO5263397 可促进清醒并抑制啮齿动物和非人类灵长类动物的非快速眼动（NREM）和快速眼动（REM）睡眠。我们检验了以下假设，即 TAAR1 对睡眠/觉醒调节的影响部分归因于 DA 释放。雄性 C57BL6/J 小鼠（n = 8）在 ZT5.5 时腹腔内给予 D1R 拮抗剂 SCH23390、D2R 拮抗剂 eticlopride、D1R + D2R 拮抗剂混合物或生理盐水，30 min 后经口给予 RO5263397 或载体。EEG、EMG、皮下温度和活动在 8 种处理中进行记录，睡眠结构在给药后 6 h 进行分析。如前所述，RO5263397 增加了觉醒，延迟了 NREM 和 REM 睡眠的开始。D1、D2 和 D1 + D2 预处理减少了 RO5263397 给药后 1-2 h 的觉醒，但只有 D1 拮抗剂显著减少了 TAAR1 介导的 NREM 潜伏期延长。D1 或 D2 拮抗剂均未影响 TAAR1 介导的 REM 睡眠抑制。这些结果表明，尽管 TAAR1 对觉醒的影响部分通过 D2R 介导，但 D1R 激活在逆转 TAAR1 介导的 NREM 睡眠潜伏期延长中发挥作用。相比之下，TAAR1 介导的 REM 睡眠抑制似乎不涉及 D1R 或 D2R 机制。
