Ontogeny of dopamine D 1 and D 2 receptor subtypes in rat basal ganglia: a quantitative autoradiographic study

Abstract

The ontogeny of D 1 and D 2 dopamine (DA) receptors in rat basal ganglia was examined by quantitative autoradiography using the iodinated ligands [ 125I]SCH 23982 and [ 125I]iodobenzamide ([ 125I]IBZM), respectively. Temporal and spatial differences in the development of the receptor subtypes were observed. Scatchard transformation of saturation isotherms conducted at postnatal day 10 (P10) and P60, showed that there was no age-related change in the affinity of [ 125I]SCH 23982 binding to D 1 receptors ( K d = 2.6 nM) but there was a significant increase in the B max (771 compared to 2032 fmol/mg protein, P = 0.002). A statistically significant difference in K d was noted between ages P10 and P60 for [ 125I]IBZM labelling of D 2 receptors (0.62 vs 1.00 nM, respectively, P < 0.01). A significant increase in the B max (211 and 721 fmol/mg protein, P < 0.01) was also observed. D 1 receptors were visible as distinct patches at P1. The highest density was found in the ventrolateral caudate-putamen (CPu). By P5 the patches were found in all subregions of the CPu and nucleus accumbens. Between P7 and P10 the binding became distinctly less patchy due to a marked increase in the density of D 1 receptors in non-patch (matrix) regions. Adult levels of receptor were seen by P30. The concentration of DA (measured by HPLC) and binding of [ 3H]mazindol to DA uptake sites in whole striatum showed similar and nonlinear increases with age. The age-related change in the topography of binding sites for [ 3H]mazindol was similar to that of D 1 receptors at the same ages. Both D 2 receptors and [ 3H]hemicholinium-3 (HC-3) binding to high affinity transport sites for choline developed initially in the dorso-lateral CPu. Their topography was largely overlapping but distinct from that of the D 1 receptor. D 2 receptors were not consistently observed until P3 in the CPu, and zones of enriched binding were aligned with zones of low density for D 1 receptors. The density of D 2 receptors reached adult levels by P30. The differential development of the DA receptors was also evident in the substantia nigra (SN) and globus pallidus (GP). D 1 receptors were found in SN prior to the appearance of D 2 receptors and throughout development the density was greater in pars reticulata than in pars compacta, whereas the density of D 2 receptors was higher in the pars compacta. At all ages the density of D 1 receptors was greater than the density of D 2 receptors in the GP and reached adult levels before reaching it in the CPu or SN. These findings suggest that D 1 and D 2 receptors develop independently of each other in the basal ganglia. Moreover, their ontogeny is related to different phases of the development of the patch and matrix compartments: (1) an increase in D 1 receptors in the patch compartment related to an increase in the density of [ 3H]mazindol sites, (2) an increase in D 2 receptors in the matrix related to maturation of [ 3H]HC-3 binding, (3) a later phase in which an increase in D 1 receptors in the matrix correlated with an increase in the density of [ 3H]mazindol sites in that compartment.