Abstract
Introduction
Circadian rhythms in mammals depend upon the cyclic oscillations of transcriptional/translational feedback loops in pacemaker cells of the suprachiasmatic nucleus. The rise and fall of clock-related proteins is a function of synthesis and degradation, the latter involving phosphorylation by casein kinase Iε and δ.
Objective
Earlier studies by our lab described the actions of a selective CKIε/δ inhibitor, PF-670462, on circadian behavior in rats; the present work extended these studies to a diurnal species, Cynomolgus monkeys.
Materials and methods
General cage activity was used to estimate the circadian rhythms of eight telemeterized monkeys under baseline conditions and following s.c. doses of PF-670462.
Results and discussion
Consolidated bouts of activity were noted during periods of light with a repeating period length of roughly 24 h based on their onset. Reassessment in constant dim light (42 vs. 450 lx) again yielded period lengths of 24 h, in this instance revealing the animals' endogenous rhythm. PF-670462 (10–100 mg/kg s.c.) produced a dose-dependent phase delay in much the same manner as that observed previously in rats. Dosing occurred 1.5 h prior to lights-off, roughly coincident with peaking levels of PER protein, a primary substrate of CKIε/δ.
Conclusions
These findings suggest that the time of dosing, when held constant in both the monkey and rat studies, produced nearly identical effects despite the subjects' diurnal or nocturnal preference. Importantly, these changes in rhythm occurred in the presence of light, revealing the drug as a powerful zeitgeber in a non-human primate and, by extension, in man.
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Acknowledgments
The authors would like to extend their thanks to the Non-Human Primate Staff of Comparative Medicine (Brett Greenland, Gwen Haggett, Carl Johnson, Christopher Olszewski, John Deschenes, Douglas Albot, Lori Clay, Terry Field Jr., John Aspinwall, Michael Birkbeck, Gerald McElwee, Robert Vuoto, Larry Matney, Michael LaBreque, Doug Pasqualini, Kevin Foss, Jodi Osowski, and Dr. Keith Fowler) for their assistance with the Cynomolgus monkeys in this study.
Conflicts of interest
During the time that this research was completed, all authors of this manuscript were receiving compensation as employees of Pfizer Inc. and/or possessed a financial holding in the company.
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Sprouse, J., Reynolds, L., Swanson, T.A. et al. Inhibition of casein kinase I ε/δ produces phase shifts in the circadian rhythms of Cynomolgus monkeys. Psychopharmacology 204, 735–742 (2009). https://doi.org/10.1007/s00213-009-1503-x
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DOI: https://doi.org/10.1007/s00213-009-1503-x