Brain
glutamate overactivity is well documented in
Parkinson's disease (PD) and antiglutamatergic drugs have been proposed to relieve PD symptoms and decrease
dyskinesias.
Metabotropic glutamate receptors are topics of recent interest in PD. This study investigated the effects of the
metabotropic glutamate receptors type 5 (mGluR5) antagonists MPEP and MTEP on motor behavior in monkeys with a
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) lesion to model PD and treated with
L-Dopa the gold standard
therapy. Six Macaca fascicularis
MPTP monkeys were initially treated repeatedly with
L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores but also induced
dyskinesias. Then, a dose-response of MPEP and MTEP (1.5-30 mg/kg) administered 15 and 30 min respectively prior to
L-Dopa, showed that the antiparkinsonian activity of
L-Dopa was generally maintained as measured with locomotion and antiparkinsonian scores as well as the onset and duration of the
L-Dopa response. Interestingly the mean
dyskinesia score during all the duration of the
L-Dopa motor effect, the 1 h peak period
dyskinesias scores as well as the maximal
dyskinesias scores were dose-dependently reduced with both drugs reaching statistical significance
at 10 and 30 mg/kg. Our results showed a beneficial antidyskinetic effect of blocking mGluR5 in
L-Dopa-treated
MPTP monkeys. This supports the
therapeutic use of an mGluR5 antagonist to restore normal brain
glutamate neurotransmission in PD and decrease
dyskinesias.