Chronic Delta(9)-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteinsin rat brain

Chronic treatment of rats with Delta(9)-tetrahydro-cannabinol (Delta(9)-THC ) results in tolerance to its acute behavioral effects. In a previous study , 21-day Delta(9)-THC treatment in rats decreased cannabinoid activation of G proteins in brain, as measured by in vitro autoradiography of guanosine- 5'-O-(3-[S-35]thiotriphosphate) ([S-35]GTP gamma S) binding. The present st udy investigated the time course of changes in cannabinoid-stimulated [S-35 ]GTP gamma S binding and cannabinoid receptor binding in both brain section s and membranes, following daily Delta(9)-THC treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time-dependent decreases in WIN 55 212-2-stimulated [S-35]GTP gamma S and [H-3]WIN 55212-2 binding in cerebell um, hippocampus, caudate-putamen, and globus pallidus, with regional differ ences in the rate and magnitude of down-regulation and desensitization. Mem brane binding assays in these regions showed qualitatively similar decrease s in WIN 55212-2-stimulated [S-35]GTP gamma S binding and cannabinoid recep tor binding (using [H-3]SR141716A), and demonstrated that decreases in liga nd binding were due to decreases in maximal binding values, and not ligand affinities. These results demonstrated that chronic exposure to Delta(9)-TH C produced time-dependent anti region-specific downregulation and desensiti zation of brain cannabinoid receptors, which may represent underlying bioch emical mechanisms of tolerance to cannabinoids.