Sodium ion modulates D 2 receptor characteristics of dopamine agonist and antagonist binding sites in striatum and retina

Abstract

Na+ influences binding of both dopamine [D] agonists and antagonists to D2 receptors in [rat and bovine] striatum and retina. Na+ markedly potentiates the loss of high-affinity agonist binding due to the GTP analog p[NH]ppG. 2-Amino-6,7-dihydroxy-1,2,3,4-tetrahydro[5,8-3H]naphthalene ([3H]ADTN) binds exclusively to an agonist conformation of D2 receptor in both and retina, distinct from the antagonist conformation labeled by [3H]spiroperidol or [3H]domperidone in striatum, or by [3H]spiroperidol in retina. Na+ is not required for interaction of [3H]ADTN or antagonist radioligand sites with the selective D2 agonist LY-141865 [trans-4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-[3,4-g]quinoline], the D2 antagonist doperidone or nonselective dopamine agonists or antagonists. Na+ is necessary for high affinity interaction of those radioligand sites with the D2 antagonists molindone and metoclopramide. With Na+ present, striatal sites for [3H]ADTN, [3H]spiroperidol and [3H]domperidone have similar affinities for antagonist, but only [3H]ADTN sites have high affinity for agonists. Na+ further decreases the low affinity of dopamine agonists for [3H]spiroperidol binding sites. Na+ enhances [3H]spiroperidol and decreases [3H]ADTN binding. Na+ alone causes bound [3H]ADTN to dissociate from at least 30% of striatal and 50% of retinal sites, and, with Na+ present, [3H]ADTN rapidly dissociates from the remaining sites upon addition of p[NH]ppG. Evidently D2 receptors in striatum and retina exist in distinct but interconvertible conformational states, with different properties depending on the presence or absence of Na+ and of guanine nucleotide. [Some of the drugs studied are neuroleptic and/or antipsychotic agents.].