PATCH-CLAMP STUDIES ON THE KINETICS AND SELECTIVITY OF N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISM BY MEMANTINE (1-AMINO-3,5-DIMETHYLADAMANTAN)

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-D-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2-33 mu M) concentration-dependently antagonized responses to NMDA 100 mu M with an IC50 of 2.92+/-0.05 mu M. In contrast, current responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA 50-100 mu M) and gamma-amino butyric acid (GABA 10 mu M) were unaffected by Memantine 8 mu M. Memantine 8 mu M caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1-100 mu M) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1-100 mu M) also selectively antagonized responses to NMDA (40 mu M) in the cortical wedge preparation with IC50 of 12.9+/-1.5 mu M.