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.