Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism.

Metabotropic glutamate receptors (mGluRs) have recently been considered as potential pharmacological targets in the treatment of neurodegenerative disorders and particularly in parkinsonism. Within the basal ganglia, receptors of group I (mGluR1 and mGluR5) are widely expressed; the present study was thus aimed at blocking these receptors in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease in the rat. Considering the prominent expression of mGluR5, we have used the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to target these receptors. In rats trained to quickly depress a lever after a visual cue, bilateral lesions of the dopaminergic nerve terminals in the striatum produced severe akinetic deficits, which were expressed by increases in delayed responses and reaction times. Acute MPEP injection (1.5, 3, and 6 mg/kg, i.p.) had no effect, whereas chronic administration, ineffective in a control group, significantly reversed the akinetic deficits. Alleviation of these deficits was seen after 1 week of treatment, and the preoperative performance was fully recovered after a 3 week treatment of MPEP at all doses. Chronic MPEP also induced ipsilateral rotation in the unilateral 6-OHDA circling model. However, no effect was seen of MPEP (1.5, 3, or 6 mg/kg, i.p.) on haloperidol-induced catalepsy (1 mg/kg, i.p.). Altogether, these results suggest a specific role of mGluRs in the regulation of extrapyramidal motor functions and a potential therapeutic value for mGluR5 antagonists in the treatment of Parkinson's disease.