ΔFosB induction correlates inversely with CB₁ receptor desensitization in a brain region-dependent manner following repeated Δ⁹-THC administration

Abstract

Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.

Keywords: Cannabinoid; Caudate-putamen; G-protein; Hippocampus; Nucleus accumbens.