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The Competition Between Endogenous Dopamine and Radioligands for Specific Binding to Dopamine Receptors
Author(s) -
CUMMING PAUL,
WONG DEAN F.,
DANNALS ROBERT F.,
GILLINGS NIC,
HILTON JOHN,
SCHEFFEL URSULA,
GJEDDE ALBERT
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04185.x
Subject(s) - raclopride , dopamine , endogenous agonist , chemistry , agonist , medicine , endocrinology , dopamine receptor , dopamine receptor d2 , amphetamine , striatum , dopamine agonist , receptor , pharmacology , dopamine receptor d1 , biology , biochemistry
A bstract : 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 ‐[ 3 H]propylnorapomorphine ([ 3 H]NPA), than on the binding of the D 2,3 antagonist [ 11 C]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 [ 11 C]raclopride,and for [ 3 H]NPA.Relative to these baseline values after dopamine depletion, saline‐treatment decreased the p B of [ 3 H]NPA by one‐half, while the p B of [ 11 C]raclopride declined by only one‐third. Amphetamine decreased the p B of [ 3 H]NPA to a greater extent than that of [ 11 C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [ 3 H]NPA than for [ 11 C]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.