Circadian Periods of Sensitivity for Ramelteon on the onset of Running-wheel Activity and the Peak of Suprachiasmatic Nucleus Neuronal Firing Rhythms in C3H HeN Mice

• Published in: Chronobiology international 2011-02, Vol.28 (1), p.31-38
• Main Authors: Rawashdeh, Oliver, Hudson, Randall L., Stepien, Iwona, Dubocovich, Margarita L.
• Format: Article
• Language: English
• Subjects: Animals; Circadian Rhythm - drug effects; Circadian Rhythm - physiology; Circadian rhythms; Indenes - pharmacology; Indenes - therapeutic use; Male; Melatonin; Melatonin - pharmacology; Melatonin - physiology; Melatonin receptors; Mice; Mice, Inbred C3H; Motor Activity - drug effects; Motor Activity - physiology; Phase response curve; Ramelteon; Receptors, Melatonin - agonists; Running; Sleep Initiation and Maintenance Disorders - drug therapy; Suprachiasmatic nucleus; Suprachiasmatic Nucleus - drug effects; Suprachiasmatic Nucleus - physiology
• ISSN: 0742-0528; 1525-6073
• DOI: 10.3109/07420528.2010.532894

Ramelteon, an MT1 MT2 melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90 µg mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H HeN mice. The PRC for ramelteon resembles that for melatonin in C3H HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8-CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6 ± 0.29 h, n = 3) and at CT2 phase delays (−3.2 ± 0.12 h, n = 6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7 ± 0.15 h, n = 4, p