In order to study the effects of chronic in vivo valproic acid administration on ERK-1/2 signaling pathway, and to elucidate the molecular mechanisms underlying the therapeutic effects of valproic acid, male Wistar rats were divided into two groups (each 20 animals), one group was treated with valproic acid chow (3.6 g/kg) for 4 weeks, the other group had access to normal chow as control. By the end of the 4th week, rat brains were removed immediately on decapitation and dissected on ice, and the hippocampus and frontal cortex were obtained. The total proteins or nuclear proteins of rat brain hippocampus and frontal cortex were prepared. Levels of the phosphorylated, active forms of MEK,ERK-1/2,RSK1,CREB and expression levels of Bcl-2 were assayed by Western blot analysis. DNA binding activity of transcriptional factor AP1 was determined by EMSA. Valproic acid increased the activities of MEK,ERK-1/2,RSK1,CREB and AP1, and up-regulated the expression of Bcl-2 in rat brain hippocampus and frontal cortex. These data suggest chronic treatment of valproic acid activates ERKs signaling pathway and up-regulates the expression of Bcl-2 proteins in central nerve system(CNS), which may associate with the therapeutic efficacy of valproic acid in the treatment of manic-depressive illness.