title: Statistical Parametric Mapping reveals ligand and region-specific activation of G-proteins by CB1 receptors and non-CB1 sites in the 3D reconstructed mouse brain.
abstract: CB(1) receptors mediate the CNS effects of Delta(9)-tetrahydrocannabinol and synthetic cannabinoids. Previous studies have investigated cannabinoid-mediated G-protein activity in a subset of brain regions thought to mediate the behavioral effects of cannabinoids, but a detailed regional comparison of the effects of multiple ligands has not been conducted. This study used a novel approach, Statistical Parametric Mapping (SPM), to analyze 3D reconstructed brain images derived from agonist-stimulated [(35)S]GTPgammaS autoradiography in a whole-brain unbiased manner. SPM analysis demonstrated regional differences in the relative efficacies of cannabinoid agonists methanandamide (M-AEA), CP55,940 (CP) and WIN55,212-2 (WIN) in CB(1)(+/+) mouse brains. To assess the potential contribution of novel cannabinoid binding sites, experiments were performed in CB(1)(-/-) mouse brains. SPM analysis revealed that the aminoalkylindole WIN, but not the bicyclic cannabinoid CP or the endocannabinoid analogue M-AEA, stimulated [(35)S]GTPgammaS binding in cortex, hippocampus, hypothalamus, amygdala, cerebellum and certain brainstem areas (dorsal tegmental complex and locus coeruleus). No differences between WIN-stimulated G-protein activity and basal activity were found in basal ganglia. Pharmacological experiments using the CB(1) antagonist SR141716A in CB(1)(+/+) mice showed that SR141716A blocked WIN-stimulated G-protein activity in all brain regions, suggesting that it binds to both CB(1) and putative non-CB(1) sites. These studies show ligand and region-specific cannabinoid-mediated G-protein activity at both CB(1) and non-CB(1) sites and demonstrate that SPM is a powerful approach for the analysis of reconstructed brain imaging data derived from agonist-stimulated [(35)S]GTPgammaS autoradiography.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Nguyen
authors.forename: D E
authors.initials: DE
authors.lastname: Selley
authors.forename: L J
authors.initials: LJ
authors.lastname: Sim-Selley
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D019204:GTP-Binding Proteins / Q000378:metabolism*; D021621:Imaging, Three-Dimensional / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D043884:Receptor, Cannabinoid, CB1; D019204:GTP-Binding Proteins
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