Modulation of [3H]quinpirole binding at striatal D2 dopamine receptors by a monoamine oxidaseA-like site -: Evidence from radioligand binding studies and D2 receptor- and MAOA-deficient mice

[H-3]Quinpirole is a dopamine agonist with high affinity for the D-2 and D-3 dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [H-3]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [H-3]quinpirole or that allosterically modulates [H-3]quinpirole binding. To determine whether the D-2 receptor is essential for [H-3]quinpirole binding and/or modulation of [H-3]quinpirole binding by MAOIs, D-2 receptor-deficient mice were studied. [H-3]Quinpirole binding was decreased in D-2 receptor-deficient mice to 3% of that observed in wild-type controls indicating that [H-3]quinpirole binding is associated with the D-2 dopamine receptors. Then, in an attempt to label the site mediating the modulation of [H-3]quinpirole binding, binding of the MAOI [H-3]Ro 41-1049 was characterized in rat striatal membranes. [H-3]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [H-3]quinpirole binding (Spearman r=0.976) and MAO(A) activity. To determine whether MAO(A) plays a role in the modulation of [H-3]quinpirole binding by MAOIs, MAO(A)- deficient mice were examined. In these mice, [H-3]Ro-41-1049 binding was decreased to 7% of wild-type control. [H-3]Spiperone binding was unaltered. Spiperone-displaceable [H-3]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [H-3]quinpirole binding in MAO(A)- deficient animals was inhibited by Ro 41-1049 similar to wild-type. [H-3]Ro-41-1049 binding was not decreased in D-2 receptor-deficient mice. These data suggest that [H-3]Ro-41-1049 labels multiple sites and that MAOIs modulate [H-3]quinpirole binding to the D-2 receptor via interactions at a novel, non-MAO binding site with MAO(A)-like pharmacology. (C) 2001 Elsevier Science Inc. All rights reserved.