Reversal of Δ⁹-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors

Tolerance develops to the pharmacological effects of Δ⁹- 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.