TY - JOUR T1 - Effect of Chronic Administration of<em>R</em>-(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-<em>de</em>]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone Mesylate (WIN55,212-2) or Δ<sup>9</sup>-Tetrahydrocannabinol on Cannabinoid Receptor Adaptation in Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 36 LP - 44 DO - 10.1124/jpet.102.035618 VL - 303 IS - 1 AU - Laura J. Sim-Selley AU - Billy R. Martin Y1 - 2002/10/01 UR - http://jpet.aspetjournals.org/content/303/1/36.abstract N2 - Agonist efficacy may influence the magnitude of neuroadaptation in response to chronic drug exposure. Chronic administration of either Δ9-tetrahydrocannabinol (THC), a partial agonist, orR-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2), a full agonist, for G protein activation produces tolerance to cannabinoid-mediated behaviors. The present study examined whether chronic administration of maximally tolerated doses of Δ9-THC and WIN55,212-2 produces similar cannabinoid receptor desensitization and down-regulation. Mice were treated with escalating doses of agonist for 15 days, with final doses of 160 mg/kg Δ9-THC and 48 mg/kg WIN55,212-2. Tolerance to cannabinoid-mediated hypoactivity, hypothermia, and antinociception was found after treatment with Δ9-THC or WIN55,212-2. In autoradiographic studies, cannabinoid-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding was significantly decreased in all regions of Δ9-THC- and WIN55,212-2-treated brains. In addition, Δ9-THC-treated brains showed greater desensitization in some regions than WIN55,212-2-treated brains. Concentration-effect curves for cannabinoid-stimulated [35S]GTPγS binding confirmed that decreases in the hippocampus resulted from loss of maximal effect in both WIN55,212-2- and Δ9-THC-treated mice. In the substantia nigra, theEmax decreased and the EC50value increased for agonist stimulation of [35S]GTPγS binding in Δ9-THC-treated mice. [3H]N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) binding was decreased in all brain regions in Δ9-THC- and WIN55,212-2-treated mice, with no difference between treatment groups. These results demonstrate that chronic treatment with either the partial agonist Δ9-THC or the full agonist WIN55,212-2 produces tolerance to cannabinoid-mediated behaviors, as well as cannabinoid receptor desensitization and down-regulation. Furthermore, Δ9-THC produced greater desensitization than WIN55,212-2 in some regions, indicating that agonist efficacy is one determinant of cannabinoid receptor desensitization in brain. The American Society for Pharmacology and Experimental Therapeutics ER -