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.