Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.
This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration 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 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.
Dubocovich
M L
ML
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA. dubo@nwu.edu
Yun
K
K
Al-Ghoul
W M
WM
Benloucif
S
S
Masana
M I
MI
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002940:Circadian Rhythm / Q000502:physiology*; D006224:Cricetinae; D003624:Darkness; D006801:Humans; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014162:Transfection; D014363:Tryptamines / Q000494:pharmacology*
C112803:4-phenyl-2-acetamidotetralin; C114459:4-phenyl-2-propionamidotetraline; D016376:Oligonucleotides, Antisense; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C057154:luzindole; D008550:Melatonin