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Circadian rhythm entrainment with melatonin, melatonin receptor antagonist S22153 or their combination in mice
1INSERM E 0354 'Chronothérapeutique des Cancers', Université Paris XI, Hôpital Paul Brousse, 94807 Villejuif Cedex, France. li@vjf.inserm.fr
Abstract:
The ability of daily melatonin and the melatonin receptor antagonist, S22153, to entrain circadian system function was investigated in mice with atypical melatonin rhythm. B6D2F(1) mice were first synchronized to a LD 12:12 for approximately 2 wk, then exposed to continuous light (LL) until study completion. After 10-18 days of LL exposure, mice received daily subcutaneous (s.c.) melatonin at a dose of 0.1, 1 or 10 mg/kg/day (exp. 1) or daily intraperitoneal (i.p.) S22153 (20 mg/kg/day) with or without melatonin (1 mg/kg/day, exp. 2) at subjective zeitgeber time (ZT) 10 for 19 days. Then all the mice were exposed to LL for another 10 days. Spectral analysis showed that initial LL lengthened the period of both rhythms by approximately 1.5 hr as compared with LD 12:12. No entrainment of either rhythm was found in controls. Conversely, daily melatonin-only, S22153-only or their combination set the temperature and activity periods to approximately 24 hr and produced a significant increase of the circadian amplitude of both rhythms as compared with controls. However, after treatment withdrawal, the dominant period lengthened to approximately 25.5 hr in mice receiving either melatonin or S22153. On the contrary, the period remained close to 24 hr for the 10 days following withdrawal of combined S22153 and melatonin. Such sustained pharmacological resetting of circadian function could display therapeutic potential against external resynchronization resulting from defective photoperiodic entrainment.
Insights
Daily melatonin and its antagonist S22153 can reset circadian rhythms in mice. Combined treatment sustained a 24-hour rhythm, suggesting therapeutic potential for circadian disorders.
Area of Science:
- Chronobiology
- Pharmacology
- Neuroscience
Background:
- Circadian rhythms regulate physiological processes, but disruptions can occur.
- Melatonin is a key hormone in circadian regulation.
- Atypical melatonin rhythms can impair the body's internal clock.
Purpose of the Study:
- To investigate the effects of daily melatonin and a melatonin receptor antagonist (S22153) on circadian system function in mice.
- To determine if these agents can entrain or reset circadian rhythms under constant light conditions.
- To assess the sustained effects of these treatments after withdrawal.
Main Methods:
- Mice were exposed to constant light (LL) to disrupt normal circadian rhythms.
- Daily administration of melatonin (0.1, 1, or 10 mg/kg) or S22153 (20 mg/kg) with or without melatonin.
- Circadian rhythms of temperature and activity were monitored using spectral analysis.
- Treatments were administered for 19 days, followed by a 10-day withdrawal period under LL.
Main Results:
- Constant light exposure lengthened the natural circadian period by approximately 1.5 hours.
- Melatonin, S22153, or their combination successfully reset activity and temperature rhythms to approximately 24 hours.
- These treatments significantly increased the amplitude of circadian rhythms.
- While melatonin or S22153 alone led to period lengthening after withdrawal, the combined treatment maintained a near 24-hour period.
Conclusions:
- Daily administration of melatonin and/or S22153 can effectively entrain circadian rhythms in mice.
- The combination of melatonin and S22153 demonstrated a sustained resetting effect on circadian function.
- This sustained pharmacological resetting offers potential therapeutic applications for conditions involving defective photoperiodic entrainment and circadian disruption.
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