The effects of delta 9-tetrahydrocannabinol and other cannabinoids on cAMP accumulation in synaptosomes.
The effects of delta 9-THC and other cannabinoids on cAMP levels in synaptosomes from mouse brains were investigated in order to determine whether cannabinoids produced their behavioral effects through alterations in adenylate cyclase. delta 9-THC (0.01-10 microM) did not significantly alter basal cAMP levels, whereas delta 9-THC and other cannabinoids were able to alter forskolin-stimulated cAMP levels in synaptosomes. In general, three kinds of responses were observed. Some cannabinoids displayed a modest, concentration-dependent decrease in cAMP levels, producing significant inhibition between 1-10 microM. Other cannabinoids, including delta 9-THC and delta 8-THC, appeared to produce a biphasic effect in that inhibition of cAMP was observed only at a single concentration. Finally, some analogs were unable to significantly alter forskolin-stimulated cAMP. There was not a clear relationship between the ability of the cannabinoids to alter cAMP levels in synaptosomes and the behavioral effects observed in mice. However, it was demonstrated that the analogs which are the most potent in producing cannabimimetic effects in mice were the analogs which inhibited cAMP in a concentration-dependent manner. While cannabinoids were able to alter cAMP levels in synaptosomes, the ability to alter cAMP levels does not appear to be absolutely necessary for the production of cannabinoid effects in mice.
Little
P J
PJ
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
Martin
B R
BR
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism*
D002186:Cannabinoids; D005576:Colforsin; D013759:Dronabinol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases