Memantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons

•Whole cell currents were recorded in dopamine neurons from slices of rat midbrain.•Currents evoked by bath-applied NMDA were compared to synaptic NMDA currents.•Memantine was more potent for blocking bath-applied NMDA currents.•The GluN2C/2D antagonist DQP-1105 mimicked memantine but MK-801 did not.•Memantine selectively blocks extrasynaptic NMDA receptors, likely to be GluN2C/2D.

Recent studies suggest that selective block of extrasynaptic N-methyl-d-aspartate (NMDA) receptors might protect against neurodegeneration. We recorded whole-cell currents with patch pipettes to characterize the ability of memantine, a low-affinity NMDA channel blocker, to block synaptic and extrasynaptic NMDA receptors in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. Pharmacologically isolated NMDA receptor-mediated EPSCs were evoked by electrical stimulation, whereas synaptic and extrasynaptic receptors were activated by superfusing the slice with NMDA (10 µM). Memantine was 15-fold more potent for blocking currents evoked by bath-applied NMDA compared to synaptic NMDA receptors. Increased potency for blocking bath-applied NMDA currents was shared by the GluN2C/GluN2D noncompetitive antagonist DQP-1105 but not by the high-affinity channel blocker MK-801. Our data suggest that memantine causes a selective block of extrasynaptic NMDA receptors that are likely to contain GluN2C/2D subunits. Our results justify further investigations on the use of memantine as a neuroprotective agent in Parkinson׳s disease.