SELECTIVE MT2 MELATONIN RECEPTOR ANTAGONISTS BLOCK MELATONIN-MEDIATEDPHASE ADVANCES OF CIRCADIAN-RHYTHMS

This study demonstrates the involvement of the MT2 (Mel(1b)) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin, In situ hybridization histochemistry with digoxigenin-labe led oligonucleotide probes revealed for the first time the expression of mt(1) and MT2 melatonin receptor mRNA within the suprachiasmatic nu cleus of the C3H/HeN mouse. Melatonin (0.9 to 30 mu g/mouse, s.c.) adm inistration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 mu g/mou se; 0.98+/-0.08 h (n=15) maximal advance at 9 mu g/mouse], Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 mu/mouse, s.c.) nor luzindole (300 mu g/mouse, s.c.), which shows 25-f old higher affinity for the MTS than the mt(1) subtype, affected the p hase of circadian activity rhythms when given alone at CT 10, All thre e antagonists, however, shifted to the right the dose-response curve t o melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 mu g melatonin, This is the first study to demonstrate th at melatonin phase advances circadian rhythms by activation of a membr ane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circad ian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selectiv e analogs for the treatment of circadian sleep and mood-related disord ers.-Dubocovich, M. L., Yun, K., Al-Ghoul, W. M., Benloucif, S., Masan a, M, I. Selective MT2 melatonin receptor antagonists block melatonin- mediated phase advances of circadian rhythms.