Reversal of delta 9-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors.
Tolerance develops to the pharmacological effects of Delta9-tetrahydrocannabinoid (THC) following repetitive administration. Adaptations in signaling pathways involved in tolerance to THC-induced behaviors are not understood. The objective of our study was the evaluation of kinase involvement in the expression of tolerance to the above four THC-induced behaviors. Kinase inhibitors that specifically inhibit cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG), calmodulin-dependent protein kinase (PKC) and src tyrosine kinase were tested for reversal of tolerance to THC's effects. PKG and PKC inhibitors did not reverse tolerance in any behavioral measure. Src tyrosine kinase inhibition reversed tolerance to only the hypoactive effects of THC. PKA inhibition reversed tolerance to all measures, although the doses of inhibitor and time-course of inhibition varied among behaviors. Thus, our data suggest that PKA activity plays a major role in THC-induced tolerance, and that THC produces its multiple effects through different signaling pathways.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980613, MCV Station, Richmond, VA 23298-0613, USA.
Caroline E
CE
Bass
Sandra P
SP
Welch
Billy R
BR
Martin
D000818:Animals; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D013759:Dronabinol; D011494:Protein Kinases