Activation of NMDA receptors in substantia nigra pars compacta (SNc) dopaminergic neurones induces a voltage-dependent burst firing (Johnson et al., 1992) that regulates dopamine release in the striatum. However, excessive activation of NMDA receptors generates oxidative stress and may cause excitotoxic cell death of dopamine neurones. This has been hypothesized to contribute to disease progression in PD (Blandini et al., 2000). Compared with other NMDA receptor open channel blockers, memantine is well tolerated clinically (Lipton, 2006) and has potential therapeutic utility for acute and chronic neurodegenetative diseases including stroke, acute trauma, Parkinson’s disease, and Huntington’s disease (Lipton, 2006). Since external Mg2+ and memantine both bind in the NMDA receptor channel, Mg2+ and memantine might compete for binding. We have used patch-clamp whole-cell recording methods to quantify the memantine block of NMDA receptors in the absence of and in the presence of physiological concentrations of external Mg2+ in 300 μm thick brain slices from 7 day old rats. Responses to high concentration (0.1 mM) or low concentration (0.02 mM) NMDA and 0.01 mM glycine in the presence of TTX (100 nM) with 3mM ATP and 1mM GTP in the pipette solution were recorded and the voltage-dependence of the net whole-cell NMDA current evoked during voltage ramps (-100 mV to +40 mV of 2 seconds duration) in the presence of 5 μM or 50 μM memantine and in the absence or in the present of 1 mM Mg2+ were quantified using simple and trapping channel block models. Memantine inhibits NMDA receptors with higher potency (IC50 = 6 μM) when the agonist concentration is higher (0.1 mM NMDA) and has less potency (IC50 = 15 μM) at low concentrations of agonist (0.02 mM NMDA). In the absence of external Mg2+, memantine showed less voltage-dependence (δ=0.55-0.6) than Mg2+ (δ=0.82) suggesting a shallower binding site within the channel. Interestingly, as previously described by Sobolevsky et al. (1998) in hippocampal neurons, the total block was reduced during co-application of memantine (50 μM) with 1 mM external Mg2+, compared to with 1 mM Mg2+ alone (n = 8). These results are not consistent with simple competition between memantine and external Mg2+ for access to a channel binding site but can be described by models (Sobolevsky & Koshelev, 1998) that have two binding sites in the channel.