HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dubocovich, M. L. Articles by Masana, M. I. Search for Related Content PubMed PubMed Citation Articles by Dubocovich, M. L. Articles by Masana, M. I.

Selective MT₂ melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms

^a Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Drug Discovery Program, Northwestern University Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611–3008, USA

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-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 µg/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 µg/mouse; 0.98±0.08 h (n=15) maximal advance at 9 µg/mouse]. Neither the selective MT₂ melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 µ/mouse, s.c.) nor luzindole (300 µg/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 µg 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., Yun, K., Al-Ghoul, W. M., Benloucif, S., Masana, M. I. Selective MT₂ melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J. 12, 1211–1220 (1998)

Key Words: melatonin receptors • suprachiasmatic nucleus • C3H/HeN mouse • luzindole • 4P-ADOT • 4P-PDOT • mt₁ • Mel_1a • Mel_1b

This article has been cited by other articles:

				B. J. Prendergast MT1 Melatonin Receptors Mediate Somatic, Behavioral, and Reproductive Neuroendocrine Responses to Photoperiod and Melatonin in Siberian Hamsters (Phodopus sungorus) Endocrinology, February 1, 2010; 151(2): 714 - 721. [Abstract] [Full Text] [PDF]

				V. Cernysiov, N. Gerasimcik, M. Mauricas, and I. Girkontaite Regulation of T-cell-independent and T-cell-dependent antibody production by circadian rhythm and melatonin Int. Immunol., January 1, 2010; 22(1): 25 - 34. [Abstract] [Full Text] [PDF]

				K. Nishiyama, Y. Shintani, K. Hirai, and S.-i. Yoshikubo Molecular Cloning and Pharmacological Characterization of Monkey MT1 and MT2 Melatonin Receptors Showing High Affinity for the Agonist Ramelteon J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 855 - 863. [Abstract] [Full Text] [PDF]

				S. Yasuo, T. Yoshimura, S. Ebihara, and H.-W. Korf Melatonin Transmits Photoperiodic Signals through the MT1 Melatonin Receptor J. Neurosci., March 4, 2009; 29(9): 2885 - 2889. [Abstract] [Full Text] [PDF]

				H. G. Richter, C. Torres-Farfan, J. Garcia-Sesnich, L. Abarzua-Catalan, M. G. Henriquez, M. Alvarez-Felmer, F. Gaete, G. E. Rehren, and M. Seron-Ferre Rhythmic Expression of Functional MT1 Melatonin Receptors in the Rat Adrenal Gland Endocrinology, March 1, 2008; 149(3): 995 - 1003. [Abstract] [Full Text] [PDF]

				R. E. Mistlberger and D. J. Skene Nonphotic Entrainment in Humans? J Biol Rhythms, August 1, 2005; 20(4): 339 - 352. [Abstract] [PDF]

				K. Hirai, M. Kita, H. Ohta, H. Nishikawa, Y. Fujiwara, S. Ohkawa, and M. Miyamoto Ramelteon (TAK-375) Accelerates Reentrainment of Circadian Rhythm after a Phase Advance of the Light-Dark Cycle in Rats J Biol Rhythms, February 1, 2005; 20(1): 27 - 37. [Abstract] [PDF]

				S. M. W Rajaratnam, B. Middleton, B. M Stone, J. Arendt, and D.-J. Dijk Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans J. Physiol., November 15, 2004; 561(1): 339 - 351. [Abstract] [Full Text] [PDF]

				M. J. GERDIN, M. I. MASANA, M. A. RIVERA-BERMUDEZ, R. L. HUDSON, D. J. EARNEST, M. U. GILLETTE, and M. L. DUBOCOVICH Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin FASEB J, November 1, 2004; 18(14): 1646 - 1656. [Abstract] [Full Text] [PDF]

				C. Torres-Farfan, H. G. Richter, A. M. Germain, G. J. Valenzuela, C. Campino, P. Rojas-Garcia, M. L. Forcelledo, F. Torrealba, and M. Seron-Ferre Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland J. Physiol., February 1, 2004; 554(3): 841 - 856. [Abstract] [Full Text] [PDF]

				M. J. Gerdin, M. I. Masana, D. Ren, R. J. Miller, and M. L. Dubocovich Short-Term Exposure to Melatonin Differentially Affects the Functional Sensitivity and Trafficking of the hMT1 and hMT2 Melatonin Receptors J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 931 - 939. [Abstract] [Full Text] [PDF]

				T. Mutoh, S. Shibata, H.-W. Korf, and H. Okamura Melatonin modulates the light-induced sympathoexcitation and vagal suppression with participation of the suprachiasmatic nucleus in mice J. Physiol., February 15, 2003; 547(1): 317 - 332. [Abstract] [Full Text] [PDF]

				X. Jin, C. von Gall, R. L. Pieschl, V. K. Gribkoff, J. H. Stehle, S. M. Reppert, and D. R. Weaver Targeted Disruption of the Mouse Mel1b Melatonin Receptor Mol. Cell. Biol., February 1, 2003; 23(3): 1054 - 1060. [Abstract] [Full Text] [PDF]

				C. Torres-Farfan, H. G. Richter, P. Rojas-Garcia, M. Vergara, M. L. Forcelledo, L. E. Valladares, F. Torrealba, G. J. Valenzuela, and M. Seron-Ferre mt1 Melatonin Receptor in the Primate Adrenal Gland: Inhibition of Adrenocorticotropin-Stimulated Cortisol Production by Melatonin J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 450 - 458. [Abstract] [Full Text] [PDF]

				M. I. Masana, S. Doolen, C. Ersahin, W. M. Al-Ghoul, S. P. Duckles, M. L. Dubocovich, and D. N. Krause MT2 Melatonin Receptors Are Present and Functional in Rat Caudal Artery J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 1295 - 1302. [Abstract] [Full Text] [PDF]

				M. A. Ayoub, C. Couturier, E. Lucas-Meunier, S. Angers, P. Fossier, M. Bouvier, and R. Jockers Monitoring of Ligand-independent Dimerization and Ligand-induced Conformational Changes of Melatonin Receptors in Living Cells by Bioluminescence Resonance Energy Transfer J. Biol. Chem., June 7, 2002; 277(24): 21522 - 21528. [Abstract] [Full Text] [PDF]

				M. I. Masana and M. L. Dubocovich Melatonin Receptor Signaling: Finding the Path Through the Dark Sci. Signal., November 6, 2001; 2001(107): pe39 - pe39. [Abstract] [Full Text] [PDF]

				L. Brydon, L. Petit, P. Delagrange, A. D. Strosberg, and R. Jockers Functional Expression of MT2 (Mel1b) Melatonin Receptors in Human PAZ6 Adipocytes Endocrinology, October 1, 2001; 142(10): 4264 - 4271. [Abstract] [Full Text] [PDF]

				C. S. Nelson, M. Ikeda, H. S. Gompf, M. L. Robinson, N. K. Fuchs, T. Yoshioka, K. A. Neve, and C. N. Allen Regulation of Melatonin 1a Receptor Signaling and Trafficking by Asparagine-124 Mol. Endocrinol., August 1, 2001; 15(8): 1306 - 1317. [Abstract] [Full Text] [PDF]

				D. L. Drazen, D. Bilu, S. D. Bilbo, and R. J. Nelson Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1476 - R1482. [Abstract] [Full Text] [PDF]

				A. E. Hunt, W. M. Al-Ghoul, M. U. Gillette, and M. L. Dubocovich Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock Am J Physiol Cell Physiol, January 1, 2001; 280(1): C110 - C118. [Abstract] [Full Text] [PDF]

				X.-M. Li, X.-H. Liu, E. Filipski, G. Metzger, P. Delagrange, J.-P. Jeanniot, and F. Levi Relationship of atypical melatonin rhythm with two circadian clock outputs in B6D2F1 mice Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R924 - R930. [Abstract] [Full Text] [PDF]

				S. Benloucif, M. I. Masana, K. Yun, and M. L. Dubocovich Interactions between Light and Melatonin on the Circadian Clock of Mice J Biol Rhythms, August 1, 1999; 14(4): 281 - 289. [Abstract] [PDF]

				S. Doolen, D. N. Krause, and S. P. Duckles Estradiol modulates vascular response to melatonin in rat caudal artery Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1281 - H1288. [Abstract] [Full Text] [PDF]