Wakefulness Induced by TAAR1 Partial Agonism in Mice Is Mediated Through Dopaminergic Neurotransmission

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 (n = 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.