Effect of MT₁ melatonin receptor deletion on melatonin‐mediated phase shift of circadian rhythms in the C57BL/6 mouse

Abstract

In the mouse suprachiasmatic nucleus (SCN), melatonin activates MT1 and MT2 G-protein coupled receptors, which are involved primarily in inhibition of neuronal firing and phase shift of circadian rhythms. This study investigated the ability of melatonin to phase shift circadian rhythms in wild type (WT) and MT1 melatonin receptor knockout (KO) C57BL/6 mice. In WT mice, melatonin (90 microg/mouse, s.c.) administered at circadian time 10 (CT10; CT12 onset of activity) significantly phase advanced the onset of the circadian activity rhythm (0.60 +/- 0.09 hr, n = 41) when compared with vehicle treated controls (-0.02 +/- 0.07 hr, n = 28) (P < 0.001). In contrast, C57 MT1KO mice treated with melatonin did not phase shift circadian activity rhythms (-0.10 +/- 0.12 hr, n = 42) when compared with vehicle treated mice (-0.12 +/- 0.07 hr, n = 43). Similarly, in the C57 MT1KO mouse melatonin did not accelerate re-entrainment to a new dark onset after an abrupt advance of the dark cycle. In contrast, melatonin (3 and 10 pm) significantly phase advanced circadian rhythm of neuronal firing in SCN brain slices independent of genotype with an identical maximal shift at 10 pm (C57 WT: 3.61 +/- 0.38 hr, n = 3; C57 MT(1)KO: 3.45 +/- 0.11 hr, n = 4). Taken together, these results suggest that melatonin-mediated phase advances of circadian rhythms of neuronal firing in the SCN in vitro may involve activation of the MT2 receptor while in vivo activation of the MT1 and possibly the MT2 receptor may be necessary for the expression of melatonin-mediated phase shifts of overt circadian activity rhythms.

Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORβ knockout

“…In mice, activation of MT 1 or MT 2 melatonin receptors mediate two distinct responses: inhibition of neuronal firing (MT 1 ) and phase shifts of neuronal firing rhythms in the SCN in vitro (MT 2 ) (9,20,23). However, phase shift of overt activity rhythms in vivo appears to require activation of MT 1 receptors (9).…”

“…In the suprachiasmatic nucleus, inhibition of neuronal activity is mediated through activation of MT 1 melatonin receptors (23), while phase shifts of neuronal firing rhythms in vitro require activation of the MT 2 melatonin receptors (9,19,20). However, paradoxically, phase shift of overt circadian rhythms of activity in vivo requires activation of MT 1 receptors, as this effect is absent in MT 1 knockout mice (9,19). Initially, melatonin was suggested as the natural ligand of retinoid orphan receptor ␤ (ROR␤); however, further research did not confirm this finding (4).…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…These results suggested a role for an endogenous pineal product (e.g., melatonin) on circadian entrainment; however, the mechanism of this phenomenon is still unclear. Mice with genetic deletion of the MT 1 , MT 2 , or MT 1 /MT 2 melatonin receptors show no circadian phenotype in experiments reported so far (Liu et al, 1997;Jin et al, 2003;Dubocovich et al, 2005;Dubocovich, 2007). Mice lacking the MT 1 melatonin receptor display depression-like behavior in the swimming test and deficits in sensory gating as demonstrated in the acoustic startle/prepulse inhibition (Weil et al, 2006).…”

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…Melatonin is secreted into the third ventricle (3V) CSF, which is in direct contact with the pinealocytes; at night, during peak melatonin synthesis, the CSF concentration is 15-20× that of plasma [110,174]. The hormone is transferred by CSF to the SCN, other hypothalamic regions, the hippocampus, and choroid plexuses, where there are high affinity MT1 receptors [56]. Lateral ventricle (LV) melatonin concentrations have been reported to be far lower than 3V melatonin concentrations; this observation has been used in part to argue that 3V melatonin is not coming from recirculation via the plasma and choroid plexuses but rather through direct secretion into the pineal recess [159,183].…”