Differential modulation of dopamine D1-receptor binding and mRNA expression in the basal ganglia by the D1-receptor antagonist,SCH-23390

Dopamine D₁-receptor binding in the basal ganglia is differentially regulated by subtype nonspecific dopamine antagonists such as the antipsychotic, Fluphenazine. The purpose of the present study was to determine the relative contributions of D₁ and D₂ receptor systems in the regulation of basal ganglia D₁-receptor binding. Rats were injected twice daily for 21 days with saline, the D₁-receptor antagonist, SCH-23390, the D₂-receptor antagonist, Raclopride, or both SCH-23390 and Raclopride. Dopamine D₁-receptor levels (as indicated by [¹²⁵I]SCH-23982 binding) and mRNA expression were measured using receptor autoradiographic and in situ hybridization histochemical techniques. [¹²⁵I]NCQ-298 binding to D₂-receptors was also measured as a positive control for the effects of Raclopride. SCH-23390 administration independently increased [¹²⁵I]SCH-23982 binding in a region-dependent manner with the greatest increases occurring in the entopeduncular nucleus. SCH-23390 also increased D₁-receptor mRNA expression in specific striatal subregions suggesting that increases in binding were related to changes in receptor synthesis. In addition, Raclopride independently enhanced D₂ binding with comparable increases observed in extrastriatal regions and increases of a lesser magnitude in the striatum. These data show that the modulation of basal ganglia D₁-receptor binding observed in animals treated with nonselective antagonists is due primarily to the blockade of D₁-receptors. The differential enhancement in basal ganglia D₁ binding observed after D₁-receptor blockade may be due to anatomical or phenotypic heterogeneity within the population of striatal D₁-receptor synthesizing neurons. Similarly, the differential enhancement in striatal and extrastriatal D₂-receptor binding may be due to differences in the regulation of striatal and extrastriatal D₂-receptor synthesizing neurons. Synapse 30:38–48, 1998. © 1998 Wiley-Liss, Inc.