Sleep-Wake Regulation Is Altered in Mice Lacking Trace Amine-Associated Receptor 1

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 possibly glutamatergic activity. Selective TAAR1 partial agonists exhibit pro-cognitive, antidepressant- and antipsychotic-like properties in both rodents and non-human primates, suggesting TAAR1 as a novel target for the treatment of neurological and psychiatric disorders. We previously showed that TAAR1 partial agonism causes a dose-dependent increase in wakefulness in rats, suggesting that TAAR1 is a previously-unrecognized component of an endogenous wake-modulating system. Here, we tested the hypothesis that endogenous TAAR1 tone contributes to the normal regulation of sleep and wakefulness. TAAR1 knock-out mice (KOs) and their wild-type (WT) littermates were instrumented for EEG and EMG recording and implanted with inductive telemetry transmitters for monitoring locomotor activity (LMA) and core body temperature. Following recovery, animals were recorded continuously under 12:12 LD conditions. Compared to WT mice, KOs exhibited increased LMA in the late dark phase. Immediately following lights-on, KOs exhibited a rapid decrease in LMA compared to WTs, in conjunction with shorter latencies to both NREM and REM sleep. In WT mice, the selective TAAR1 partial agonist RO5263397 administered p.o. at ZT6 caused a dose-dependent increase in waking comparable to caffeine; this effect was absent in KOs. While preliminary, these results suggest that TAAR1 influences sleep and waking in a complex manner, possibly through modulation of monoaminergic signaling. Abnormal levels of TAs have long been associated with neuropsychiatric disorders; altered TAAR1 regulation of the monoamines may therefore underlie the sleep disturbances that are frequently comorbid with mental illness.