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 int raperitoneally twice a day for 6 days, tolerance to its analgesic effect ap peared to be complete. Chronic exposure to Delta(9)-THC caused a significan t reduction in CB1 receptor binding in all brain areas that contain this re ceptor. 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 b y the significant increase of cAMP levels and PKA activity in the areas wit h receptor down-regulation (cerebellum, striatum and cortex). We propose th at the increase in cAMP cascade is part of the biochemical basis of cannabi noid tolerance. (C) 2000 Elsevier Science Ltd. All rights reserved.