Subchronic haloperidol increases CB1 receptor binding and G protein coupling in discrete regions of the basal ganglia

The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D-2 receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB1 receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of H-3-raclopricle and quinpirole-induced guanosine 5'-O-(gamma-[S-35]thio)triphosphate ([S-35]GTP gamma S) in the striatum when compared to that measured in control animals. This increased D-2 receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB, receptor binding and CP55,940-stimulated [S-35]GTP gamma S in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus palliclus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB1 receptor-stimulated [S-35]GTP gamma S bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB1 receptor or [S-35]GTP gamma S binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB1 receptor supersensitivity after haloperidol treatment. (c) 2005 Wiley-Liss, Inc.