Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP-dependent protein kinase activity in some rat brain regions.

When Delta(9)-tetrahydrocannabinol (Delta(9)-THC,15 mg/kg) was injected intraperitoneally twice a day for 6 days, tolerance to its analgesic effect appeared to be complete. Chronic exposure to Delta(9)-THC caused a significant reduction in CB1 receptor binding in all brain areas that contain this receptor. Cannabinoid receptor density was markedly reduced in the cerebellum (52%), hippocampus (40%) and globus pallidum (47%) compared to 30% in the cortex and striatum. Chronic exposure enhanced the cAMP pathway, as shown by the significant increase of cAMP levels and PKA activity in the areas with receptor down-regulation (cerebellum, striatum and cortex). We propose that the increase in cAMP cascade is part of the biochemical basis of cannabinoid tolerance.