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.
Rubino
T
T
Institute of Pharmacology, Faculty of Sciences, University of Milan, via Vanvitelli 32/A, 20129, Milan, Italy.
Vigano'
D
D
Massi
P
P
Spinello
M
M
Zagato
E
E
Giagnoni
G
G
Parolaro
D
D
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D013759:Dronabinol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases