Melatonin Does Not Affect the Stress-Induced Phase Shifts of Peripheral Clocks in Male Mice

Repeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin (Mel) is thought to be a circadian clock-controlled signal that might play a role in synchronizing peripheral rhythms, in addition to its direct suppressing effects on the stress axis. In this study we test whether Mel can reduce the social-defeat stress-induced phase shifts in peripheral rhythms, either by modulating circadian phase or by modulating the stress axis. Two experiments were performed with male Mel-deficient C57BL/6J mice carrying the circadian reporter gene construct (PER2::LUC). In the first experiment, mice received night-restricted (ZT11-21) Mel in their drinking water, resulting in physiological levels of plasma Mel peaking in the early dark phase. This treatment facilitated re-entrainment of the activity rhythm to a shifted light-dark cycle, but did not prevent the stress-induced (ZT21-22) reduction of activity during stress days. Also, this treatment did not attenuate the phase-delaying effects of stress in peripheral clocks in the pituitary, lung, and kidney. In a second experiment, pituitary, lung, and kidney collected from naive mice (ZT22-23), were treated with Mel, dexamethasone (Dex), or a combination of the two. Dex application affected PER2 rhythms in the pituitary, kidney, and lung by changing period, phase, or both. Administering Mel did not influence PER2 rhythms nor did it alleviate Dex-induced delays in PER2 rhythms in those tissues. We conclude that exogenous Mel is insufficient to affect peripheral PER2 rhythms and reduce stress effects on locomotor activity and phase changes in peripheral tissues.