Grant: Travel Awards - Institute Community Support

Melatonin is a neurohormone produced in the pineal gland which is involved in numerous physiological functions, including sleep regulation, via its receptors MT1 and MT2. The Locus Coeruleus (LC) nucleus contain critical wakefulness-promoting neurons which discharge at highest rates during wakefulness (W), and lower rates during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. However, the activity of melatonin MT1 receptor in the LC is poorly understood due to the lack of receptor-selective compounds. Here we investigate the role of the first selective MT1 receptor partial agonist UCM871 in the sleep-wake cycle, and the activity of the noradrenergic (NE) neurons in the LC over a 24-hour period. To assess the effects of UCM871 on the sleep-wake cycle, electroencephalograms (EEG) were recorded in free-moving rats for a period of 24 h, within which a subcutaneous injection of vehicle (veh) or UCM871 (7, 14 and 21 mg/kg) was administrated every 4 hours. To assess the localization and the distribution of MT1 receptors in LC-NE neurons, we used immunolabeling with receptor-specific antibodies. In-vivo single unit extracellular recordings of NE neurons were performed following the administration of veh or UCM871 (3.5, 7, 10 and 14 mg/kg, i.v.) to investigate role of the NE neurons of LC in sleep activity. Rats treated with UCM871 at 14 mg/kg s.c. exhibited an increase in the duration (min) of REM sleep (veh: 96.6; UCM871: 119.7, p<0.05) in light phase. Furthermore, immunolabeling showed a higher co-expression of MT1 receptors with NE neurons in dark and light phase. Finally, electrophysiology showed that LC-NE neurons' activity decreased in both phases with the administration of UCM871 at 10 and 14 mg/kg. Conclusion: MT1 receptors play an important role in REM sleep and in adrenergic function, but in a distinct manner. While MT1 activation in LC by UCM871 is pronounced in the dark phase, the effect in the REM sleep is higher during the light phase.