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Selective MT 2 Melatonin Receptor Antagonist Modulates Circadian Activity via Inhibition of the Endogenous Melatonin Signal in the East Bound Jet Lag Model
Author(s) -
Sosa Jennifer,
Lipinski Jennie,
Tsakalidou Vassiliki,
Papanastasiou Ioannis,
Sakellaropoulou Aikaterini,
Tsotinis Andrew,
Dubocovich Margarita
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01911
Subject(s) - melatonin , entrainment (biomusicology) , circadian rhythm , endocrinology , medicine , antagonist , receptor , receptor antagonist , endogeny , circadian clock , melatonin receptor , analysis of variance , biology , chemistry , rhythm
Activation of melatonin receptors facilitates re‐entrainment of circadian activity rhythms following an advance of the dark onset. In an eastbound jet lag model, administration of exogenous melatonin, at the new dark onset, accelerates re‐entrainment via activation of the MT 1 receptor (Dubocovich et al., 2005). Conversely, melatonin proficient mice (C3H/HeN) with a targeted deletion of the MT 2 receptor (MT 2 KO), but not the MT 1 receptor (MT 1 KO), experience a deceleration in re‐entrainment, probably due to impairment of the endogenous melatonin facilitated signaling mediated by activation of the MT 2 receptor (Pfeffer et al., 2012). To further elucidate the functional modulatory role of melatonin receptors on the synchronization of the circadian clock, we assessed locomotor activity rhythms in C3H/HeN mice in response to pharmacological intervention to determine the ability of the MT 2 selective antagonist, ATBT‐23 (hMT 1 /hMT 2 Ki=190), to decelerate re‐entrainment by blocking the MT 2 receptor, thus mimicking the MT 2 KO. Male C3H/HeN mice in a 12/12 L/D cycle were subjected to an eastbound jet lag paradigm in which Vehicle (30% ethanol/saline, s.c) or ATBT‐23 (1 mg/kg in Vehicle, s.c) were administered on three consecutive days at the new dark onset following an abrupt 6‐hour advance of the L/D cycle. The number of days to re‐entrain and re‐entrainment rates (hrs/day) were analyzed by two‐way ANOVA (Tukey's post hoc test) and a mixed effect two‐way repeated measure ANOVA (Sidak's post hoc test), respectively. WT (7.54±0.33 days, n=28) and MT 1 KO (7.36±0.54 days, n=14) mice treated with vehicle did not show a significant difference in the number of days necessary to attain re‐entrainment. However, MT 2 KO (11.92±0.40 days, n=13) mice, treated with vehicle, took significantly longer to re‐entrain when compared to WT and MT 1 KO mice (p<0.0001). This deceleration of re‐entrainment in the MT 2 KO was reproduced by ATBT‐23 , which decelerated the rate of re‐entrainment in both WT (p<0.0001, n=25) and MT 1 KO (p<0.01, n=12) males, increasing the number of days to re‐entrain to 9.76±0.46 (p<0.01) and 10.00±0.63 (p<0.05) days, respectively. ATBT‐23 (n=14) did not significantly affect the number of days to re‐entrain in MT 2 KO mice, suggesting deceleration of re‐entrainment is not mediated by the MT 1 receptor. The present study suggests that ATBT‐23 decelerates re‐entrainment of circadian activity rhythms by blocking the potent acceleration of re‐entrainment by endogenous melatonin via action on the MT 2 receptor. Therefore, selective MT 2 melatonin receptor antagonists can potentially be used to delay advanced circadian rhythms, as observed in depression and advance sleep phase disorders, when administered at proper circadian times.