Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to Δ9-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.