VOLTAGE-DEPENDENT AND USE-DEPENDENT BLOCK BY 1-METHYL-4-PHENYLPYRIDINIUM ION (MPP(+)) OF N-METHYL-D-ASPARTATE-ACTIVATED CURRENTS IN RAT HIPPOCAMPAL-NEURONS

The effects of 1-methyl-4-phenylpyridinium ion (MPP(+)) on N-methyl-D-aspartate (NMDA) receptor-channel complex were studied in rat hippocampal neurons using intracellular- and whole-cell voltage clamp-recording techniques. Intracellular recordings were made from CA1 pyramidal cells of rat hippocampal slices in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 mu M) and picrotoxin (PTX; 50 mu M) which block non-NMDA and GABA(A) receptors, respectively. Superfusion of MPP(+) reversibly decreases the pharmacologically isolated NMDA receptor-mediated excitatory postsynaptic potential (EPSP(NMDA)) in a concentration-dependent manner. In other experiments, we observed that MPP(+) attenuated NMDA-evoked whole-cell currents in a voltage- and use-dependent manner and was not dependent on the extracellular glycine or spermine concentration on neurons freshly dissociated from rat hippocampi CA1 region. These results suggest that MPP(+), applied at micromolar concentrations, is a non-competitive NMDA receptor antagonist in rat hippocampal neurons.