Wakefulness Induced by TAAR1 Partial Agonism is Mediated Through Dopaminergic Neurotransmission.

Autor:	Park S; Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA., Heu J; Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA., Hoener MC; Neuroscience, Ophthalmology and Rare Diseases DTA, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Kilduff TS; Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 14. Date of Electronic Publication: 2024 Sep 14.
DOI:	10.1101/2024.09.09.612122
Abstrakt:	Trace amine-associated receptor 1 (TAAR1) is known to negatively regulate dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in mice, rats, and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake were due, at least 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 (10% DMSO in DI water) at ZT6 per os . EEG, EMG, subcutaneous temperature, and activity were recorded in each mouse across the 8 treatment conditions and sleep architecture was analyzed for 6 hours post-dosing. Consistent with our previous reports, RO5263397 increased wakefulness as well as the latency to NREM and REM sleep. D1, D2, and D1+D2 pretreatment reduced RO5263397-induced wakefulness during the first 1-2 hours after dosing, but only the D1+D2 combination attenuated the wake-promoting effect of RO5263397 from ZT6-8, mostly by increasing NREM sleep. Although D1+D2 antagonism blocked the wake-promoting effect of RO5263397, only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected TAAR1-mediated suppression of REM sleep. These results suggest that, whereas 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. By contrast, TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms. Competing Interests: Conflicts of Interest: Drs. Park, Ms. Heu and Dr. Kilduff reported no biomedical financial interests or potential conflicts of interest. Dr. Hoener is an employee of F. Hoffmann-La Roche Ltd.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu