Ramelteon Phase Advanced Circadian Rhythms of Neuronal Firing in The Suprachiasmatic Nucleus (SCN) Brain Slice by Activation of Both MT 1 and MT 2 Melatonin (MLT) Receptors

Abstract

Ramelteon, a high affinity MT1 (Ki: 14 pM) and MT2 (Ki: 104 pM) MLT receptor agonist promotes sleep and phase shifts circadian rhythms (Curr Opinion Inv Drugs 1:–121, 2005). This study determined the MLT receptor type(s) involved in ramelteon-mediated phase shifts of spontaneous circadian rhythms of neuronal firing in SCN brain slices from C3H/HeN mice using single-unit recordings. SCN brain slices from wild type (WT) mice showed a peak of neuronal firing at circadian time (CT) 6.1 ± 0.1 h (n=5) [CT12: activity onset for host mice], which was advanced by ramelteon (10 pM, 10 min) application on day 1 at CT 10 to CT 1.2 ± 0.7 h (n=4, p < 0.0001) on day 2. Ramelteon significantly advanced the peak of neuronal firing in SCN from WT (4.9 ± 0.7 h, n=4), MT1KO (3.4 ± 0.15 h, n=5) and MT2KO (1.6 ± 0.4 h, n=3), but not from MT1MT2KO mice. Ramelteon-mediated phase advance in SCN brain slices from WT mice was MLT receptor specific and resulted from activation of MT2 receptors with a smaller contribution from MT1 receptors. MLT (10 pM), however, induced phase advances of identical magnitude via activation of MT2 receptors in SCN from WT (2.7 ± 0.15h, n=4) and MT1 KO (3 ± 0.1h, n=4) mice, but did not affect phase in SCN from MT2KO or MT1MT2KO mice (Hudson et al., Neuropshychopharmacol 30:, 2005). We conclude that ramelteon uncovered a functional MT1 melatonin receptor in the SCN also involved in phase shifting circadian rhythms. Supported by a Takeda Investigator-Sponsored Research Grant 06-016R.