title: 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 (WIN55,212-2) or delta(9)-tetrahydrocannabinol on cannabinoid receptor adaptation in mice.
abstract: 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-[(35)S]thio)triphosphate ([(35)S]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 [(35)S]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 EC(50) value increased for agonist stimulation of [(35)S]GTPgammaS binding in Delta(9)-THC-treated mice. [(3)H]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.
authors.affiliation: Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Richmond, USA. ljsimsel@hsc.vcu.edu
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.forename: Billy R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D048588:Benzoxazines; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002186:Cannabinoids / Q000037:antagonists & inhibitors; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009928:Organ Specificity; D010880:Piperidines / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000493:pharmacokinetics; D011859:Radiography; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology*; D000077285:Rimonabant; D013462:Sulfur Radioisotopes
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D000077285:Rimonabant