An inhibitor of casein kinase 1 ε/δ partially normalizes the manic-like behaviors of the ClockΔ19 mouse

Behav Pharmacol. 2012 Aug;23(4):392-6. doi: 10.1097/FBP.0b013e32835651fd.

Abstract

Bipolar disorder is a terrible and debilitating disease with limited treatment options. Circadian rhythm disruptions are prominent in bipolar subjects, and studies have shown that rhythm stabilization through psychosocial interventions can improve their symptoms. Furthermore, mice with a mutation in one of the central circadian proteins, CLOCK, have severely disrupted rhythms along with a behavioral profile that closely resembles human mania. A compound has been developed (CK01, similar to PF-670462) that inhibits the activity of casein kinase 1 (CK1), a critical protein involved in the timing of the molecular clock. Previous studies have shown that PF-670462 and other similar compounds are capable of entraining and stabilizing rhythms in arrhythmic animals. Here we show that chronic administration of CK01 leads to a reversal of the anxiety-related behavior, and partial reversal of the depression-related phenotypes of the Clock mutant mouse. This drug had no significant effects on the behavior of wild-type mice at the doses tested. These results suggest that CK1ε/δ inhibitors could be viable drugs for the treatment of bipolar disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / physiopathology
  • CLOCK Proteins / genetics*
  • Casein Kinase Idelta / antagonists & inhibitors*
  • Casein Kinase Iepsilon / antagonists & inhibitors*
  • Disease Models, Animal
  • Drug Administration Schedule
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation

Substances

  • CLOCK Proteins
  • Clock protein, mouse
  • Casein Kinase Idelta
  • Casein Kinase Iepsilon