Inhibition of casein kinase I ε/δ produces phase shifts in the circadian rhythms of Cynomolgus monkeys

Abstract

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 Iepsilon and delta. Earlier studies by our lab described the actions of a selective CKIepsilon/delta inhibitor, PF-670462, on circadian behavior in rats; the present work extended these studies to a diurnal species, Cynomolgus monkeys. 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. 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 CKIepsilon/delta. 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.