Effects of chronic treatment with selective and nonselective antagonists on the subtypes of dopamine receptors

The effects of chronic blockade of D‐1, D‐2, or both subtypes of dopamine receptors on the densities and properties of the D‐1 and D‐2 subtypes of dopamine receptors were measured in rat brain. Animals were treated with 14 daily injections (i.p.) of the D‐1‐selective antagonist SCH‐23390, the D‐2‐selective antagonist sulpiride, the nonselective antagonist fluphenazine, or vehicle. Serial 32‐μm horizontal sections that included the caudate putamen were cut and alternately assigned to assays for D‐1 or D‐2 receptors. D‐1 receptors were labeled with 3H‐SKF‐83566 or 3H‐SCH‐23390, and D‐2 receptors were labeled with 3H‐spiroperidol. Scatchard analysis was performed on the saturation data measured in the head of the caudate putamen to obtain estimates of receptor density. As expected, administration of the D‐1‐selective ligand SCH‐23390 resulted in an increase in the density of D‐1 receptors by approximately 47% and had no significant effect on the density of D‐2 receptors. Similarly, administration of the D‐2‐selective ligand sulpiride resulted in an increase in the density of D‐2 receptors by 25% and had no significant effect on the density of D‐1 receptors. Thus the subtypes of dopamine receptors appear to be independently regulated after selective blockade. In contrast to the effects observed with selective antagonists, the results obtained with fluphenazine were more complex. Administration of the relatively nonselective antagonist fluphenazine resulted in an increase in the density of D‐2 receptors by 51% but had no significant effect on the density of D‐1 receptors. One explanation for this result is that up‐regulation of D‐2 receptors inhibits the regulation of D‐1 receptors, suggesting that the regulation of subtypes of dopamine receptors is not entirely independent. In support of this hypothesis, coadministration of sulpiride with SCH‐23390 attenuated the ability of SCH‐23390 to up‐regulate D‐1 receptors. To determine whether this phenomenon is observed in other brain regions, a second group of animals was chronically treated with selective and nonselective antagonists as described above, and coronal sections were cut at multiple levels of the brain. Receptors were labeled with a single concentration of either 3H‐SCH‐23390 or 3H‐spiroperidol, and the binding of the radioligands in 19 discrete brain regions was measured. The effects of these treatments on D‐1 and D‐2 receptors in most of these regions were similar to those described above for the caudat