Patch clamp studies on the kinetics and selectivity of N-methyl-d-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan) |
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Authors: | Chris G Parsons Ren Gruner Jouri Rozental John Millar David Lodge |
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Institution: | Chris G. Parsons, René Gruner, Jouri Rozental, John Millar,David Lodge |
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Abstract: | 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 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC50 of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM 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 μM) 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 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC50 of 12.9 ± 1.5 μM. |
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Keywords: | N-methyl-d-aspartate (NMDA) (S)-α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) dizocilpine (MK-801) γ -amino butyric acid (GABA) memantine (1-amino-3 5-dimethyl-adamantan) ketamine phencyclidine (PCP) dextrorphan dextromethorphan Mg2+ patch clamp culture superior colliculus hippocampus |
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