L-3,4-Dihydroxyphenylalanine (l-DOPA), the gold standard therapy for Parkinson disease (PD), is associated with motor fluctuations and dyskinesias. This study sought to prevent the development of l-DOPA-induced dyskinesias (LID) with the metabotropic glutamate receptor type 5 (mGlu5 receptor) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in the de novo treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model. MPTP-lesioned monkeys were treated once daily for one month with either l-DOPA or l-DOPA + MPEP (10 mg/kg). MPEP (administered 15 min before l-DOPA) plasma concentrations were elevated during all the l-DOPA motor activation and did not accumulate during a month. The antiparkinsonian effect was maintained throughout the treatment period in MPTP-lesioned monkeys treated with l-DOPA + MPEP, while the duration of this effect decreased over time in MPTP-lesioned monkeys treated with l-DOPA alone, suggesting wearing-off. Over the month-long treatment, the mean dyskinesia score increased in l-DOPA-treated monkeys; interestingly, this increase was reduced by overall 72% in the l-DOPA + MPEP group. Mean dyskinesia scores of monkeys correlated inversely with plasma MPEP concentrations. Normal control and saline-treated MPTP-lesioned monkeys were also included for biochemical analyses. All MPTP-lesioned monkeys were extensively and similarly denervated. [(3)H]ABP688 specific binding to mGlu5 receptors increased in the putamen of l-DOPA-treated monkeys compared to control, saline or l-DOPA + MPEP-treated monkeys. Mean dyskinesia scores of MPTP-lesioned monkeys correlated positively with [(3)H]ABP688 specific binding in the putamen. This study showed a beneficial chronic antidyskinetic effect of MPEP in de novol-DOPA-treated MPTP-lesioned monkeys, supporting the therapeutic use of mGlu5 receptor antagonists in PD to prevent LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.