Effect of chronic administration of R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (IN55,212-2) or Δ9-tetrahydrocannabinol on cannabinoid receptor adaptation in mice

Agonist efficacy may influence the magnitude of neuroadaptation in response to chronic drug exposure. Chronic administration of either Delta(9)-tetrahydrocannabinol (THC), a partial agonist, or R-(+)-[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 Delta(9)-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 Delta(9)-THC and 48 mg/kg WIN55,212-2. Tolerance to cannabinoid-mediated hypoactivity, hypothermia, and antinociception was found after treatment with Delta(9-)THC or WIN55,212-2. In autoradiographic studies, cannabinoid-stimulated guanosine 5'-O-(3-[S-35]thio) triphosphate ([S-35]GTPgammaS) binding was significantly decreased in all regions of Delta(9)-THC- and WIN55,212-2-treated brains. In addition, Delta(9)-THC- treated brains showed greater desensitization in some regions than WIN55,212-2-treated brains. Concentration-effect curves for cannabinoid-stimulated [S-35]GTPgammaS binding confirmed that decreases in the hippocampus resulted from loss of maximal effect in both WIN55,212-2- and Delta(9)-THC-treated mice. In the substantia nigra, the E-max decreased and the EC50 value increased for agonist stimulation of [S-35]GTPgammaS binding in Delta(9)-THC-treated mice. [H-3]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 Delta(9)-THC- and WIN55,212-2-treated mice, with no difference between treatment groups. These results demonstrate that chronic treatment with either the partial agonist Delta(9)-THC or the full agonist WIN55,212-2 produces tolerance to cannabinoid-mediated behaviors, as well as cannabinoid receptor desensitization and down-regulation. Furthermore, Delta(9)-THC produced greater desensitization than WIN55,212-2 in some regions, indicating that agonist efficacy is one determinant of cannabinoid receptor desensitization in brain.