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Cellular mechanisms of Δ9-tetrahydrocannabinol behavioural sensitization


: Professor Daniela Parolaro, as above.


We investigated the cellular events linked to the induction of cannabinoid behavioural sensitization. In sensitized rats, autoradiographic binding studies with [3H]CP-55,940 showed a significant increase in cannabinoid receptor binding, specifically in the cerebellum, with no changes in the other brain areas where basal CB1-receptor expression is observed. In vitro autoradiography of CP-55,940-stimulated [35S]GTPγS binding provided a picture of cannabinoid receptor-mediated G protein activation. Basal [35S]GTPγS binding was not affected, whereas sensitized rats showed a significant increase of net [35S]GTPγS binding in the caudate putamen and cerebellum. Autoradiographic studies suggested that only these two areas had altered receptor functionality. We therefore focused our intracellular investigations only there, first surveying the responsiveness of the cAMP system to cannabinoids. CP-55,940 was unable to inhibit forskolin-induced cAMP accumulation in the cerebellum of sensitized animals, but no difference was observed between groups in the caudate putamen. Finally, we surveyed the levels of CREB and AP-1 binding activity, in the same two areas and found no difference in sensitized rats. The intracellular picture in sensitized rats suggests that besides the cAMP cascade, other signalling pathways may participate in the development of cannabinoid sensitization.