Activation of MT2melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock

Abstract

The aim of this study was to identify the melatonin receptor type(s) (MT 1 or MT 2) mediating circadian clock resetting by melatonin in the mammalian suprachiasmatic nucleus (SCN). Quantitative receptor autoradiography with 2-[125 I]iodomelatonin and in situ hybridization histochemistry, with either 33 P- or digoxigenin-labeled antisense MT 1 and MT 2 melatonin receptor mRNA oligonucleotide probes, revealed specific expression of both melatonin receptor types in the SCN of inbred Long-Evans rats. The melatonin receptor type mediating phase advances of the circadian rhythm of neuronal firing rate in the SCN slice was assessed using competitive melatonin receptor antagonists, the MT 1/MT 2 nonselective luzindole and the MT 2-selective 4-phenyl-2-propionamidotetraline (4P-PDOT). Luzindole and 4P-PDOT (1 nM-1 μM) did not affect circadian phase on their own; however, they blocked both the phase advances (∼4 h) in the neuronal firing rate induced by melatonin (3 pM) at temporally distinct times of day [i.e., subjective dusk, circadian time (CT) 10; and dawn, CT 23], as well as the associated increases in protein kinase C activity. We conclude that melatonin mediates phase advances of the SCN circadian clock at both dusk and dawn via activation of MT 2 melatonin receptor signaling.