0014 TRACE AMINE-ASSOCIATED RECEPTOR 1 REGULATES WAKEFULNESS, BEHAVIORAL ACTIVATION AND EEG SPECTRAL COMPOSITION

Abstract

Trace amines (TAs) are endogenous amino acid metabolites that are structurally similar to the biogenic amines. TAs are endogenous ligands for trace amine-associated receptor 1 (TAAR1), a GPCR that modulates dopaminergic, serotonergic, and glutamatergic activity. Selective TAAR1 agonists have been shown to have pro-cognitive, antipsychotic-like, anti-addiction, stress-reducing, weight-reducing, glucose-lowering and wake-promoting activities. We used Taar1 knockout (KO) and over-expressing (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 24h recording to characterize baseline sleep/wake, mice were sleep-deprived (SD) for 6h. In separate experiments, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, modafinil or vehicle p.o. Baseline wakefulness was modestly increased in OE compared to WT mice. Baseline theta (4.5-9Hz) and low gamma (30-60Hz) activity was elevated in KO compared to 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 Tb without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. By contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared to vehicle; this effect was attenuated in KO and potentiated in OE mice. Subsequent studies confirmed that motor activation and gamma band activity increases induced by caffeine or modafinil are attenuated in KO mice compared to WT. TAAR1 overexpression increases wakefulness whereas TAAR1 partial agonism strongly increases wakefulness and reduces NREM and 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. NIH R01 NS082876.