USE-DEPENDENT DEPRESSION OF SYNAPTIC NMDA RECEPTOR-MEDIATED RESPONSESBY DIZOCILPINE (MK-801)

The influence of synaptic activity on the depression of iv-methyl-D-as partate (NMDA) receptor mediated synaptic responses by the noncompetit ive blocker dizocilpine and the competitive antagonist CPP -(((R)-2-ca rboxypiperazin-4-yl)propyl-1-phosphonic acid) was examined in the rat hippocampal slice preparation. In slices superfused by a Mg2+-free med ium, both drugs, dizocilpine (2 to 100 mu M) and CPP (0.2 to 10 mu M), applied by perfusion, depressed the NMDA receptor mediated secondary population spikes (PSs) in the CA1 pyramidal cell layer. Repetitive st imulation (0,2 Hz, 5 min) greatly enhanced the depression produced by dizocilpine but was without any effect on the depression produced by C PP. In slices superfused with a normal medium. dizocilpine applied loc ally by pressure ejection (100 mu M, 380 pL, 1 s) coupled with high-fr equency stimulation (100 Hz, 1 s) prevented the appearance of multiple PSs in the subsequent 90-min period of perfusion with a Mg:e-free med ium but was ineffective when applied without concomitant stimulation. These results indicate that the synaptic NMDA receptor mediated respon ses. similar to responses evoked by exogenous NMDA agonists, are depre ssed by dizocilpine in a use-dependent manner.