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Vol. 303, Issue 1, 36-44, October 2002
9-Tetrahydrocannabinol on
Cannabinoid Receptor Adaptation in Mice
Department of Pharmacology and Toxicology and Institute for
Drug and Alcohol Studies, Virginia Commonwealth University Medical
College of Virginia, Richmond, Virginia
Agonist efficacy may influence the magnitude of neuroadaptation in
response to chronic drug exposure. Chronic administration of either
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
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
9-THC and 48 mg/kg WIN55,212-2. Tolerance to
cannabinoid-mediated hypoactivity, hypothermia, and antinociception was
found after treatment with 9-THC or WIN55,212-2. In
autoradiographic studies, cannabinoid-stimulated guanosine
5'-O-(3-[35S]thio)triphosphate
([35S]GTP
S) binding was significantly decreased in all
regions of 9-THC- and WIN55,212-2-treated brains. In
addition, 9-THC-treated brains showed greater
desensitization in some regions than WIN55,212-2-treated brains.
Concentration-effect curves for cannabinoid-stimulated
[35S]GTPS binding confirmed that decreases in the
hippocampus resulted from loss of maximal effect in both WIN55,212-2-
and 9-THC-treated mice. In the substantia nigra, the
Emax decreased and the EC50
value increased for agonist stimulation of [35S]GTPS
binding in 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
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 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, 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.
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