Effect of Δ9-tetrahydrocannabinol on phosphorylated CREB in rat cerebellum:: An immunohistochemical study

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 CBI receptors, has a role not only in motor function but also in cognition. This immunohistochemical study examines the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive component of marijuana, on the levels of phosphorylated CREB (p-CR-EB) in the rat cerebellum. Acute treatments with Delta(9)-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 CB I receptor antagonist SR 141716A. Following chronic Delta(9)-THC administration (10 mg/kg/day for 4 weeks), the density of p-CR-EB was markedly attenuated compared to controls, and this attenuation persisted 3 weeks after withdrawal from Delta(9)-THC. These data provide evidence for the involvement of cerebellar granule cells in the adaptive changes occurring during acute and chronic Delta(9)-THC exposure. This might be a mechanism by which Delta(9)-THC interferes with motor and cognitive functions. (c) 2005 Elsevier B.V. All rights reserved.