Effects of acute and chronic valproate treatments on p-CREB levels in the rat amygdala and nucleus accumbens

Abstract Valproate may exert its effects by modulating signalling pathways controlling gene expression as they are known to alter both CREB and ERK pathways in the rat hippocampus and frontal cortex. The action of valproate on these signalling pathways has not been studied yet in limbic areas such as the nucleus accumbens and the amygdala which are central for the regulation of emotional behaviors. To this aim, the effect of valproate on phosphorylated CREB (p-CREB) and ERK (p-ERK) in the amygdala and nucleus accumbens, by using immunohistochemical and Western blot analysis, was investigated. The immunohistochemistry was followed by a stereological quantification of the number of immunoreactive cells. Acute valproate (80 mg/kg, i.p.) increased the density of p-CREB-positive cells and enhanced p-CREB, but not p-ERK, protein levels in the amygdala and the accumbens. In contrast, following chronic valproate (80 mg/kg/day for 4 weeks) p-CREB and p-ERK protein levels were markedly attenuated in the amygdala, while the number of p-CREB immunoreactive cells was increased in the accumbens. These data suggest that valproate exert differential effects depending on the brain region examined, the duration and the dose of treatment. The increasing effect of chronic valproate on p-CREB levels in the accumbens is consistent with previous studies in the cortex and the hippocampus, while the decrease of amygdalar p-CREB levels might be specific to mood stabilizers compared to antidepressant drugs, and might be linked to the anti-manic action of valproate.