Valproate is now the most widely prescribed mood-stabilizing drug and is being used increasingly in the treatment of bipolar disorder. However, the mechanism of action for valproate remains unclear. Microarray analysis was used to identify genes and cellular pathways that are affected in the mouse brain after treatment with valproate at human therapeutic concentrations. This study has identified 11 genes that are differentially expressed by >or=2-fold when compared to control untreated mice. Altered expression of four of these genes was also validated by quantitative PCR analysis. Valproate was found to significantly decrease the expression of zinc finger protein of the cerebellum 1 (ZIC1) and increase the expression of Scm-related gene containing four mbt domains (SFMBT2), structural maintenance of chromosome 4-like 1 (SCM4L1), and prostate apoptosis response-4 (PAR-4). Many of the genes identified are involved in the development and function of the brain. These results indicate that valproate regulates a large number of different functional pathways in the brain. Understanding the molecular and cellular mechanisms by which valproate achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.