Increasing evidence indicates that the excessive glutamate release onto substantia nigra pars compacta (SNpc) dopaminergic neurons may play an important role in the progression of nigral degeneration. We examined the effects of chronic, systemic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, in firing activity of SNpc dopaminergic neurons in 6-hydroxydopamine (6-OHDA) partially lesioned rats. In 6-OHDA-lesioned rats treated with vehicle, injection of 6-OHDA (4 microg) into the medial forebrain bundle produced a partial lesion, 39% loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNpc. In partially lesioned rats, the electrophysiological characteristics of SNpc dopaminergic neurons showed that the firing rate of these neurons increased compared with sham-operated rats and the firing pattern also changed towards a burstier one. Chronic, systemic treatment of MPEP (3 mg/kg/day, 14 days) attenuated loss of TH-ir neurons and normalized the hyperactive firing activity in the SNpc induced by partial unilateral dopamine depletion lesions. In addition, no significant differences were found in the responsiveness of SNpc dopaminergic neurons to intravenous cumulative apomorphine in sham-operated, vehicle-treated and MPEP-treated rats, while ED50 values for apomorphine in MPEP-treated rats were decreased as compared with vehicle-treated rats. These data demonstrate that the surviving dopaminergic neurons in the SNpc are hyperactive in an experimental model of moderate Parkinson's disease (PD). In this model, chronic, systemic MPEP treatment has the neuroprotective effect and reverses the abnormal firing activity of dopaminergic neurons, suggesting that MPEP has an important implication for the treatment of PD.