The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors

The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D_2,3 agonist N-[³H]propylnorapomorphine ([³H]NPA), than on the binding of the D_2,3 antagonist [¹¹C]raclopride in living brain. The binding potential (p_B(0)), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [¹¹C]raclopride (p_B(0)^{RAC C} = 8.5), and for [³H]NPA (p_B(0)^NPA= 5.3). Relative to these baseline valuesafter dopamine depletion, saline-treatment decreased the p_B of [³H]NPA by one-half, while the p_B of [¹¹C]raclopride declined by only one-third. Amphetamine decreased the p_B of [³H]NPA to a greater extent than that of [¹¹C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [³H]NPA than for [¹¹C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.