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

Repeated Delta(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB(1)Rs) in the brain, but the magnitude of these adaptations varies among regions. CB(1)Rs 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, Delta FosB, is induced in the striatum following repeated THC administration and could regulate CB(1)Rs. To directly compare the regional profile of Delta FosB induction and CB1R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [S-35]GTP gamma S autoradiography and immunohistochemistry were performed to measure CB1R desensitization and downregulation, respectively, and Delta FosB 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. Delta FosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between Delta FosB expression and CB1R desensitization was found, such that regions with the greatest Delta FosB induction did not exhibit CB1R desensitization and areas without Delta FosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB1R co-localization with Delta FosB in cells and CB1R puncta surrounding Delta FosB-positive cells. THC-induced expression of Delta FosB was absent in the striatum of CB1R knockout mice. These data suggest that transcriptional targets of Delta FosB might inhibit CB1R desensitization and/or that Delta FosB induction could be limited by CB1R desensitization. (C) 2013 Elseviir Ltd. All rights reserved.