Dynamic modulation of NMDA-induced responses by ifenprodil in rat prefrontal cortex

Ifenprodil is known to inhibit channel opening of NMDA receptors containing the NR2B subunit. However, it has also been shown to increase NMDA receptor affinity for glutamate-site agonists, including NMDA. The coexistence of the two opposing effects may explain why ifenprodil can either enhance or suppress an NMDA response depending on the level of NMDA binding and thus the NMDA concentration. Using whole cell recordings in rat prefrontal cortical slices, we report here that the effect of ifenprodil also depends on the speed and the direction of change of NMDA concentration. As shown previously, ifenprodil increased the inward current induced by low concentrations of NMDA applied through a local Y-tube perfusion system. However, the rising phase of the current was less enhanced compared to the falling phase. Increasing the speed of rising of NMDA concentration further reduced the enhancing effect of ifenprodil. When pressure ejection was used to produce even faster NMDA responses, the entire rising phase including the peak of the response was suppressed by ifenprodil, while the falling phase remained enhanced. These results are consistent with the suggestion that ifenprodil decreases both the association and dissociation rates of NMDA from NMDA receptors, and suggest that ifenprodil affects slow and fast NMDA responses in different manners. In particular, this study suggests that ifenprodil inhibits the rising phase of a fast NMDA response by suppressing both channel opening and the association of NMDA with NMDA receptors and that this inhibition can occur even when the level of NMDA binding is low.