Effects of Chronic Treatment with D-Tetrahydrocannabinol on Cannabinoid-Stimulated [S]GTPgS Autoradiography in Rat Brain

Chronic D-tetrahydrocannabinol (D-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agoniststimulated [S]GTPgS binding to localize cannabinoid receptor-activated G-proteins after chronic D-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [S]GTPgS binding was performed in brain sections from rats treated chronically with 10 mg/kg D-THC for 21 d. Control animals received saline or an acute injection of D-THC. Acute D-THC treatment had no effect on basal or WIN 55212-2-stimulated [S]GTPgS binding. After chronic D-THC treatment, net WIN 55212-2stimulated [S]GTPgS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus pallidus, substantia nigra, and cerebellum. In contrast, chronic D-THC treatment had no effect on GABAB-stimulated [S]GTPgS binding. In membranes and brain sections, D-THC was a partial agonist, stimulating [S]GTPgS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 552122-stimulated [S]GTPgS at high concentrations. Because the EC50 of WIN 55212-2-stimulated [ S]GTPgS binding and the KD of cannabinoid receptor binding were unchanged by chronic D-THC treatment, the partial agonist actions of D-THC did not produce the decrease in cannabinoid-stimulated [S]GTPgS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic D-THC treatment.