Chronic treatment with a selective inhibitor of casein kinase I δ/ε yields cumulative phase delays in circadian rhythms

Introduction Casein kinase I ε/δ phosphorylates certain clock-related proteins as part of a complex arrangement of transcriptional/ translational feedback loops that comprise the circadian oscillator in mammals. Pharmacologic inhibition leads to a delay of the oscillations with the magnitude of this effect dependent upon the timing of drug administration. Objective Earlier studies by our lab described the actions of a selective CKI ε/δ inhibitor, PF-670462, on circadian behavior following acute dosing; the present work extended these studies to chronic once-daily treatment. Methods Gross motor activity was used to estimate the circadian rhythms of rats maintained under a 12 L:12 D cycle. PF-670462, 10 or 30 mg/kg/day s.c., was administered once daily for 20 days either at ZT6 or ZT11 (i.e., 6 or 11 h after light onset). Results Chronic administration of PF-670462, performed at a fixed time of day, produced delays in the activity onsets of rats that cumulated with the duration of dosing. Dosing at ZT11 yielded more robust delays than dosing at ZT6 in keeping with earlier phase-response analyses with this agent. Conclusions The magnitude of the shifts in activity onsets achieved with chronic dosing of PF-670462 appears to be a function of the dose and the previously established phase relationship. Its cumulative effect further suggests that the pharmacodynamic t _1/2 of the drug greatly exceeds its pharmacokinetic one. Most importantly, these changes in circadian behavior occurred in the presence of a fixed L:D cycle, confirming the drug to be a robust modulator of circadian phase in the presence of the natural zeitgeber.