Sunmee Park ¹ Jasmine Heu ¹ Gavin Scheldrup ¹ Ryan K. Tisdale ¹ Yu Sun ¹ Shun-Chieh Ma ¹ Meghan Haire ¹ Marius C. Hoener ² Thomas S. Kilduff ^1*

• ¹ Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California, United States
• ² Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland

The Trace Amine-associated Receptor (TAAR) family has nine G protein-coupled receptor (GPCR) members in mammals. TAAR1 is the most well-studied family member and has become a therapeutic target for neuropsychiatric disorders because it modulates release of dopamine, serotonin and glutamate. We have previously shown that TAAR1 partial agonists enhance wake and reduce REM sleep in mice, rats and non-human primates. Accordingly, we hypothesized that TAAR2-9 may also have a role in sleep/wake regulation. To test this hypothesis, we compared baseline sleep/wake patterns, the homeostatic response to sleep deprivation, the response to TAAR1 agonists, and one aspect of monoaminergic function between male TAAR2-9 knockout (KO) and C57BL/6J (WT) mice. KO mice exhibited lower delta and theta power and higher power in the gamma range of the EEG and had readily identifiable sleep/wake states. KO mice had 16% more NREM sleep during the dark phase and 23% more REM sleep during the light phase than WT mice, with fragmented sleep characterized by shorter Wake and REM bouts. High doses of the TAAR1 agonist RO5256390 increased Wake and reduced NREM sleep in KO mice, while RO5256390 and the partial TAAR1 agonist RO5263397 suppressed REM sleep. Elevated tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area of KO mice suggest dopaminergic involvement in these altered sleep patterns. Since sleep disruption is a characteristic of many neuropsychiatric disorders, these findings highlight the need for further elucidation of the functions of TAARs 2-9 and suggest that other TAAR family members in addition to TAAR1 may have therapeutic potential.