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NEUROPHARMACOLOGY

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to ⁹-Tetrahydrocannabinol

Department of Pharmacology and Toxicology (D.L.M., M.P.C., L.M.C., B.R.M., J.L.W., D.E.S., L.J.S.-S.) and Institute for Drug and Alcohol Studies (B.R.M., J.L.W., D.E.S., L.J.S.-S.), Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia

Chronic treatment with ⁹-tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific 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-[³⁵S]thio)triphosphate ([³⁵S]GTPS)-binding assays in brains from THC-treated mice. Agonist-stimulated [³⁵S]GTPS binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [³⁵S]GTPS 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.

Address correspondence to: Dr. Laura Sim-Selley, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980524, 1112 East Clay St., Richmond, VA 23298. E-mail: ljsimsel{at}vcu.edu