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

Beth Levant, Kimberly A. Morgan, Joy A. Ahlgren-Beckendorf, David K. Grandy, Kevin Chen, Jean C. Shih, Isabelle Seif

    Research output: Contribution to journalArticle

    14 Scopus citations

    Abstract

    [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 MAOA activity. To determine whether MAOA plays a role in the modulation of [3H]quinpirole binding by MAOIs, MAOA-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 MAOA-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 MAOA-like pharmacology.

    Original languageEnglish (US)
    Pages (from-to)229-241
    Number of pages13
    JournalLife Sciences
    Volume70
    Issue number2
    DOIs
    StatePublished - Nov 30 2001

    Keywords

    • Monoamine oxidase
    • Monoamine oxidase inhibitor
    • Quinpirole
    • Rat
    • Striatum

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Pharmacology, Toxicology and Pharmaceutics(all)

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