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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.

Several converging lines of evidence indicate that drugs of abuse may exert their long-term effects on the central nervous system by modulating signaling pathways controlling gene expression. Cannabinoids produce, beside locomotor effects, cognitive impairment through central CB1 cannabinoid receptors. Data clearly indicate that the cerebellum, an area enriched with CB1 receptors, has a role not only in motor function but also in cognition. This immunohistochemical study examines the effect of delta9-tetrahydrocannabinol (delta9-THC), the principal psychoactive component of marijuana, on the levels of phosphorylated CREB (p-CREB) in the rat cerebellum. Acute treatments with delta9-THC at doses of 5 or 10 mg/kg induced a significant increase of p-CREB in the granule cell layer of the cerebellum, an effect blocked by the CB1 receptor antagonist SR 141716A. Following chronic delta9-THC administration (10 mg/kg/day for 4 weeks), the density of p-CREB was markedly attenuated compared to controls, and this attenuation persisted 3 weeks after withdrawal from delta9-THC. These data provide evidence for the involvement of cerebellar granule cells in the adaptive changes occurring during acute and chronic delta9-THC exposure. This might be a mechanism by which delta9-THC interferes with motor and cognitive functions.