• Article

Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to Delta(9)-tetrahydrocannabinol

Chronic treatment with Delta(9)-tetrahydrocannabinol ( THC) produces tolerance to cannabinoid-mediated behaviors and regionspecific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception, and hypothermia was produced by both ramping THC-dose paradigms. Administration of 10 mg/kg THC produced less tolerance development, the magnitude of which depended upon the particular behavior. Decreases in cannabinoid-mediated G-protein activation, which varied with treatment dose and region, were observed in autoradiographic and membrane guanosine 5'-O(3-[S-35]thio)triphosphate ([S-35]GTP gamma S)-binding assays in brains from THC-treated mice. Agonist-stimulated [S-35]GTP gamma S binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [S-35]GTP gamma S binding in the caudate-putamen, nucleus accumbens, and preoptic area occurred only after administration of 10 to 30 to 60 mg/kg THC, and no change was found in the globus pallidus or entopeduncular nucleus after any treatment. Changes in the CB1 receptor B-max values also varied by region, with hippocampus and cerebellum showing reductions after all treatments and striatum/globus pallidus showing effects only at higher dosing regimens. These results reveal that tolerance and CB1 receptor adaptation exhibit similar dose-dependent development, and they are consistent with previous studies demonstrating less cannabinoid receptor adaptation in striatal circuits


McKinney, D. L., Cassidy, M. P., Collier, L. M., Martin, B. R., Wiley, J., Selley, D. E., & Sim-Selley, L. J. (2008). Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to Delta(9)-tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics, 324(2), 664-673.