Memantine does not show intracellular block of the NMDA receptor channel.
Mg2+ is known to gain access to the NMDA receptor channel from both the extra- and intracellular compartments. Memantine, being an amphiphilic substance, reaches intracellular concentrations of approximately 30 microM, which are much higher than therapeutic extracellular concentrations ( approximately 1 microM). We therefore investigated whether memantine can also block the NMDA receptor channel from the intracellular compartment. NR1a/NR2A receptors were expressed in Xenopus oocytes and in classical two electrode voltage-clamp recordings, voltage-ramps from -100 to +100 mV confirmed moderate inward rectification of NR1a/NR2A receptor control responses at positive membrane potentials above +40 mV. Patch clamp recordings from these same cells (applying 100 microM glutamate and 1 mM Mg2+) revealed similar rectification at positive potentials in cell-attached mode which disappeared after pulling an inside-out patch. Application of 1 mM Mg2+ to the intracellular side of the receptor re-introduced the rectification seen in cell-attached mode, and 5 mM Mg2+ produced much more pronounced block. In contrast, 30 microM memantine was completely unable to block the NMDA receptor from the intracellular compartment. In conclusion, intracellular block of the NMDA receptor, as reported for Mg2+, is not of significance for the therapeutic effects of memantine.