Selective MT ₂ melatonin receptor antagonists block melatonin‐mediated phase advances of circadian rhythms

Abstract

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.

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

“…Activation of MT 1 acutely inhibits the neuronal firing rate (Liu et al 1997;Gillette and Mitchell 2002;Jin et al 2003), while activation of the MT 2 phase shifts circadian rhythms of activity in vivo via activation of PKC (Dubocovich et al 1998;McArthur et al 1997;Hunt et al 2001).…”

Melatonin Transmits Photoperiodic Signals through the MT1 Melatonin Receptor

“…MT2 is also expressed in the brain including the suprachiasmatic nucleus, where it mediates the phase shifting responses to melatonin (Liu et al, 1997;Dubocovich et al, 1998). Moreover, melatonin may act on other binding sites (MT3) (Boutin et al, 2005).…”

Evaluation of the Role of Melatonin in Dietary Restriction Effects on Spatial Memory Impairment Induced by Streptozotocin (STZ) in Male Rats

“…Since measurement of melatonin level changes was hardly practical, we decided to use luzindole, an antagonist of melatonin receptors to pursue this objective. According to our findings, ICV administration of luzindole 50 µgr/kg in initial hours of dark cycles (this dose had been shown can disrupt circadian rhythms or vanish neuroprotective effect of melatonin (23,(26)(27) did not have any effect on spatial memory of STZ-treated rats. Likewise, the tendency toward improvement of spatial memory in EODF-STZ treated rats did not change by luzindole.…”