According to the ternary complex model of G-protein linkage to receptors, agonists increase the affinity of the receptors for the G protein. The model predicts that an endogenous agonist's constant of inhibition toward an agonist radioligand is lower than that toward an antagonistic radioligand. The authors hypothesized that competition from endogenous dopamine in striatum of living mice should have a greater effect on the binding of the D2,3 partial agonist N-[3H]propylnorapomorphine than on the binding of the D2,3 antagonist [11C]raclopride. The baseline binding potential (pB(0)), defined as the ratio of bound-to-unbound ligand in the absence of competition from endogenous dopamine, was simultaneously measured in mouse striatum for [11C]raclopride (pB(0)) = 8.5) and N-[3H]propylnorapomorphine (p′B(O) = 5.3). The baseline was established by treatment with α-methyl-p-tyrosine and reserpine. Relative to these baseline values in saline-treated mice, the pB of N-[3H]propylnorapomorphine decreased 52% whereas the pB of [11C]raclopride decreased only 30%, indicating greater sensitivity of the former compound to inhibition by synaptic dopamine. Furthermore, amphetamine decreased the pB of N-[3H]propylnorapomorphine to a greater extent (73%) than that of [11C]raclopride (43%) relative to the reserpine condition. For both radioligands, the occupancy of the dopamine receptors by endogenous agonist obeyed Michaelis-Menten kinetics over a wide range of agonist concentrations established by the pharmacologic treatments. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and decreased to a value 1.66 times greater for N-[3H] propylnorapomorphine than for [11C]raclopride at its highest occupancies. The results are consistent with the hypothesis that agonist binding is more sensitive than antagonist binding to competition from endogenous dopamine. Therefore, dopamine agonist ligands may be superior to benzamide antagonist ligands for the estimation of dopamine receptor occupancy by endogenous synaptic dopamine. The analysis of the effect of dopamine occupancy on the inhibition of N-[3H]propylnorapomorphine binding indicated a limited supply of G protein with a maximum ternary complex fraction of 40% of maximum agonist binding capacity.
- N-[H] propylnorapomorphine