title: Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition.
abstract: Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (Tb), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased Tbwithout affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schwartz
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Black
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fisher
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Jeremiah B
authors.initials: JB
authors.lastname: Palmerston
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Morairty
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases DTA, pRED, Roche Innovation Center Basel, F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Marius C
authors.identifier: http://orcid.org/0000-0001-6510-6250
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Thomas S
authors.identifier: http://orcid.org/0000-0002-6823-0094
authors.initials: TS
authors.lastname: Kilduff
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D002110:Caffeine; D000697:Central Nervous System Stimulants; D010080:Oxazoles; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C000596180:4-(3-fluoro-2-methylphenyl)-4,5-dihydrooxazol-2-ylamine