EFFECTS OF CHRONIC NEUROLEPTIC TREATMENTS ON DOPAMINE D-1 AND D-2 RECEPTORS - HOMOGENATE BINDING AND AUTORADIOGRAPHIC STUDIES

The antipsychotic effects of neuroleptics are believed to be mediated via dopamine D-2 receptor blockade; however, the anatomical and pharma cological targets of these drugs remain somewhat controversial. The pu rpose of this study was to examine the effects of chronic clozapine (C LZ) and haloperidol (HAL) treatments on the densities of DA D-1 and D- 2 receptors. Adult male Sprague-Dawley rats (300-350 g) were treated f or 21 days with either HAL (1 mg/kg/day, i.p.), CLZ (20 mg/kg/day, i.p .) or saline. Three days after ending the treatments, the brains were removed and used for biochemical assays of tissue DA and metabolites a s well as for receptor studies. DA D-1 and D-2 receptors were labelled with [H-3]SCH23390 and [H-3]raclopride, respectively, and measured in the neostriatum by binding studies, and in autoradiograms of forebrai n sections by quantitative densitometry. The autoradiographic measurem ents revealed significant increases in the densities of D-2 receptors in nucleus accumbens, in the medio-ventral, latero-dorsal and latero-v entral quadrants of the rostral neostriatum, in caudal neostriatum and in globus pallidus of both HAL- (28-44%) and CLZ-treated (15-85%) ani mals. The HAL-induced up-regulation of D-2 receptors in rostral and ca udal neostriatum was homogenous, but CLZ produced a more uneven increa se, with the highest absolute densities measured in latero-dorsal neos triatum, as well as with changes in the medio-dorsal rostral neostriat um. For D-1 receptors, only CLZ and not HAL, produced significant incr eases in five regions, namely nucleus accumbens (43%), latero-dorsal r ostral neostriatum (16%), caudal neostriatum (30%), globus pallidus (6 7%) and substantia nigra (12%). The observation that CLZ, contrary to HAL, also has an effect on D-1 receptor densities may explain the grea ter therapeutic and selective efficacy with fewer side-effects of this agent, in comparison to other neuroleptics. (C) 1997 Elsevier Science Ltd. All rights reserved.