Use-dependent depression of synaptic NMDA receptor mediated responses by dizocilpine (MK-801)

The influence of synaptic activity on the depression of N-methyl-D-aspartate (NMDA) receptor mediated synaptic responses by the noncompetitive blocker dizocilpine and the competitive antagonist CPP (3-((R)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) was examined in the rat hippocampal slice preparation. In slices superfused by a Mg(2+)-free medium, both drugs, dizocilpine (2 to 100 microM) and CPP (0.2 to 10 microM), applied by perfusion, depressed the NMDA receptor mediated secondary population spikes (PSs) in the CA1 pyramidal cell layer. Repetitive stimulation (0.2 Hz, 5 min) greatly enhanced the depression produced by dizocilpine but was without any effect on the depression produced by CPP. In slices superfused with a normal medium, dizocilpine applied locally by pressure ejection (100 microM, 380 pL. 1 s) coupled with high-frequency stimulation (100 Hz, 1 s) prevented the appearance of multiple PSs in the subsequent 90-min period of perfusion with a Mg(2+)-free medium but was ineffective when applied without concomitant stimulation. These results indicate that the synaptic NMDA receptor mediated responses, similar to responses evoked by exogenous NMDA agonists, are depressed by dizocilpine in a use-dependent manner.