Effects of Chronic Treatment with Δ9-Tetrahydrocannabinol on Cannabinoid-Stimulated [35S]GTPγS Autoradiography in Rat Brain

Abstract

Chronic Δ⁹-tetrahydrocannabinol (Δ⁹-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study usesin vitroautoradiography of agonist-stimulated [³⁵S]GTPγS binding to localize cannabinoid receptor-activated G-proteins after chronic Δ⁹-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [³⁵S]GTPγS binding was performed in brain sections from rats treated chronically with 10 mg/kg Δ⁹-THC for 21 d. Control animals received saline or an acute injection of Δ⁹-THC. Acute Δ⁹-THC treatment had no effect on basal or WIN 55212-2-stimulated [³⁵S]GTPγS binding. After chronic Δ⁹-THC treatment, net WIN 55212-2-stimulated [³⁵S]GTPγS 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 Δ⁹-THC treatment had no effect on GABA_B-stimulated [³⁵S]GTPγS binding. In membranes and brain sections, Δ⁹-THC was a partial agonist, stimulating [³⁵S]GTPγS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated [³⁵S]GTPγS at high concentrations. Because the EC₅₀of WIN 55212-2-stimulated [³⁵S]GTPγS binding and theK_Dof cannabinoid receptor binding were unchanged by chronic Δ⁹-THC treatment, the partial agonist actions of Δ⁹-THC did not produce the decrease in cannabinoid-stimulated [³⁵S]GTPγS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic Δ⁹-THC treatment.