Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in l-DOPA-treated parkinsonian monkeys

Abstract

Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with l-DOPA and developed dyskinesias while those treated with l-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [3H]ABP688 specific binding (mGlu5 receptors) was elevated in l-DOPA-treated MPTP monkeys compared to controls but not in those treated with l-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [3H]ABP688 specific binding. Striatal density (Bmax) of [3H]ABP688 specific binding increased in l-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [3H]Ro 25-6981 (NMDA NR1/NR2B receptors), [3H]Ro 48-8587 (AMPA receptors) but not [3H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in l-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [3H]LY341495 specific binding (mGlu2/3 receptors) decreased in l-DOPA-treated MPTP monkeys compared to controls, saline and l-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.