Melatonin receptor-mediated modulation of multiple behavioral rhythms in mice
Adamah-Biassi, Ekue Bright
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High affinity melatonin receptors are expressed in different regions of the central nervous system and modulate processes that can modify behaviors. The goal of our research was to investigate the role of endogenous melatonin by genetic disruption of melatonin receptors signaling and exogenous melatonin by pharmacological activation of the receptors in modulating the behavioral rhythms of spontaneous homecage behavioral rhythms in single housed mice. The role of endogenous melatonin was determined using wild type C57BL/6 or C3H/HeN compared to mice with disruption of the MT 1 (C57MT 1 KO or C3HMT 1 KO) and/or MT 2 (C3HMT 2 KO or C3HDOKO) receptor signaling. Mice behaviors were compared using the HomeCageScan system ( Cleversys Inc., Reston, VA ) that is capable of recording and analyzing over multiple 24 hours, 15 distinct spontaneous homecage behaviors. Behaviors assessed were activity-Like behaviors (i.e. travel distance, walk, hang, jump), exploration-Like behaviors (i.e. dig, groom, rear up, sniff, stretch), resting-like behaviors (i.e. awake, remain low, rest, twitch) and ingestion-like behaviors (i.e. drink, eat). Recording in the homecage was coupled with canonical behavioral testing including marble burying test, forced swim test, water and food measurement in the homecage. Behaviors in the homecage were analyzed using phenotypic arrays and temporal distribution analysis. C3H and C57 under 14/10 LD cycle expressed respectively a unimodal and bimodal distribution of homecage behaviors. Wheel running activity, water and food measurements correlated with timing of homecage behaviors. Subcutaneous (3 mg/kg, s.c) or oral (0.02 mg/ml, oral) melatonin treatments in C57 mice did not modify either the total 24 h magnitude or temporal distribution of homecage behaviors when compared with vehicle treatments suggesting that melatonin might not account for any of the behavioral changes between the two strains. Genotype comparison in WT and MT 1 KO C57 mice under a 14/10LD cycle showed that deletion of the MT 1 receptor transformed the bimodal profile into a unimodal one. This change is consistent from day to day in male and dependent on the estrus cycle in female. Deletion of the MT 1 and/or MT 2 receptors did neither affect the unimodal profile nor the temporal distribution of homecage behaviors in C3H mice under a 12/12LD cycle. Genetic inactivation of the MT 1 in both strain increases immobility in the forced swim and decreases marble buying behavior only in C57 mice indicating that the MT 1 melatonin receptor signaling might be involved in modulating homecage behavioral rhythms, anxiolytic and depressant-like activities. Pharmacological activation of the melatonin receptor using subcutaneous and oral administration of melatonin (3mg/kg, s.c or 0.02mg/ml, oral) or the competitive antagonist/inverse agonist luzindole (10mg/kg, s.c or 0.03mg/ml, oral) did neither modify the magnitude nor the rhythms of homecage behaviors under basal conditions in C3H mice under a 12/12LD cycle. However after a 6hr advance in the dark onset, melatonin treatment (3mg/kg, s.c) decreased while luzindole treatment increased the number of days required for the re-entrainment of wheel running activity and homecage behavioral rhythms. These results suggest that melatonin do not affect behavioral under basal conditions but can synchronize behaviors when disruption occurs. We concluded that endogenous melatonin signaling through the MT 1 receptor is important in regulating behavioral rhythms, anxiolytic and depressant-like activities while exogenous melatonin can synchronize behavioral rhythms when asynchrony occurred.