Enhancement of NMDA-induced current by the putative NR2B selective antagonist ifenprodil

Ifenprodil has been widely used as an antagonist selective for NMDA recepto rs containing the NR2B subunit. Evidence suggests, however, that ifenprodil also increases NMDA receptor affinity. Using rat brain slices, we found th at ifenprodil enhanced NMDA-induced current in both cortical and subcortica l areas examined. To test whether the effect is due to an increase in NMDA receptor affinity, we compared the effect of ifenprodil on currents induced by different concentrations of NMDA. Consistent with the hypothesis, the e nhancing effect (percent increase) was relatively constant at low NMDA conc entrations. As NMDA concentration increased, however the effect decreased. To test whether the effect is blocked when NMDA binding sites are saturated with NMDA, high concentrations of NMDA were applied. To partially block Ca 2+ influx and prevent cells fi om deteriorating, the experiments were perfo rmed in the presence of either MK801 or kynurenate, two noncompetitive anta gonists. Under such conditions, ifenprodil not only failed to potentiate NM DA currents, but consistently suppressed the current. When the same concent ration of NMDA was applied in the presence of the competitive antagonist CG P37849, ifenprodil regained its ability to potentiate NMDA currents. Furthe rmore, the higher the concentration of CGP37849 the more the NMDA current w as potentiated by ifenprodil. These results, combined with previous studies , suggest that the enhancing effect is due to an increase in NMDA receptor affinity and is specific for responses induced by low NMDA concentrations. As NMDA concentration increases, the affinity-enhancing effect decreases. C onsequently, the channel-suppressing effect becomes more prominent. (C) 200 0 Wiley-Liss, Tnc.