An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors

Mol Psychiatry. 2014 Mar;19(3):342-50. doi: 10.1038/mp.2013.12. Epub 2013 Feb 12.


Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / metabolism*
  • Bipolar Disorder / physiopathology*
  • CLOCK Proteins / genetics
  • CLOCK Proteins / physiology*
  • Cholecystokinin / biosynthesis
  • Cholecystokinin / physiology*
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lithium Chloride / pharmacology
  • Lithium Chloride / therapeutic use*
  • Male
  • Mice
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism


  • Myeloid-Lymphoid Leukemia Protein
  • Cholecystokinin
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse
  • Lithium Chloride