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

[³H]Quinpirole is a dopamine agonist with high affinity for the D₂ and D₃ dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [³H]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [³H]quinpirole or that allosterically modulates [³H]quinpirole binding. To determine whether the D₂ receptor is essential for [³H]quinpirole binding and/or modulation of [³H]quinpirole binding by MAOIs, D₂ receptor-deficient mice were studied. [³H]Quinpirole binding was decreased in D₂ receptor-deficient mice to 3% of that observed in wild-type controls indicating that [³H]quinpirole binding is associated with the D₂ dopamine receptors. Then, in an attempt to label the site mediating the modulation of [³H]quinpirole binding, binding of the MAOI [³H]Ro 41-1049 was characterized in rat striatal membranes. [³H]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [³H]quinpirole binding (Spearman r=0.976) and MAO_A activity. To determine whether MAO_A plays a role in the modulation of [³H]quinpirole binding by MAOIs, MAO_A-deficient mice were examined. In these mice, [³H]Ro-41-1049 binding was decreased to 7% of wild-type control. [³H]Spiperone binding was unaltered. Spiperone-displaceable [³H]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [³H]quinpirole binding in MAO_A-deficient animals was inhibited by Ro 41-1049 similar to wild-type. [³H]Ro-41-1049 binding was not decreased in D₂ receptor-deficient mice. These data suggest that [³H]Ro-41-1049 labels multiple sites and that MAOIs modulate [³H]quinpirole binding to the D₂ receptor via interactions at a novel, non-MAO binding site with MAO_A-like pharmacology.