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 Export

@article{citeulike:2318011, 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-[35S]thio)triphosphate ([35S]GTP[gamma]S) 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 [35S]GTP[gamma]S 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 Emax decreased and the EC50 value increased for agonist stimulation of [35S]GTP[gamma]S binding in [Delta]9-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 [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. 10.1124/jpet.102.035618}, author = {Sim-Selley, Laura J. and Martin, Billy R.}, citeulike-article-id = {2318011}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/jpet.102.035618}, citeulike-linkout-1 = {http://jpet.aspetjournals.org/cgi/content/abstract/303/1/36}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/12235230}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=12235230}, day = {1}, doi = {10.1124/jpet.102.035618}, journal = {J Pharmacol Exp Ther}, keywords = {cannabinoid, chronic}, month = {October}, number = {1}, pages = {36--44}, posted-at = {2008-02-01 05:42:39}, priority = {3}, 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}, url = {http://dx.doi.org/10.1124/jpet.102.035618}, volume = {303}, year = {2002} }

TY - JOUR ID - citeulike:2318011 L3 - citeulike-article-id:2318011 N2 - 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-[35S]thio)triphosphate ([35S]GTP[gamma]S) 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 [35S]GTP[gamma]S 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 Emax decreased and the EC50 value increased for agonist stimulation of [35S]GTP[gamma]S binding in [Delta]9-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 [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. 10.1124/jpet.102.035618 IS - 1 JF - J Pharmacol Exp Ther EP - 44 TI - 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 VL - 303 SP - 36 KW - cannabinoid KW - chronic AU - Sim-Selley, Laura AU - Martin, Billy PY - 2002/10/01/ UR - http://dx.doi.org/10.1124/jpet.102.035618 ER -