Receptor specific inhibition of N-methyl-D-aspartate stimulated 22Na flux from rat hippocampal slices by phencyclidine and other drugs

Phencyclidine inhibited the flux of 22Na from hippocampal slices of the rat stimulated by N-methyl-D-aspartate (NMDA) in a concentration-dependent manner and consistent with the subclass of excitatory amino acid receptors, with a close interaction between NMDA and phencyclidine receptors. The inhibition by phencyclidine of the NMDA-stimulated flux of 22Na was non-competitive, in contrast to that produced by D-2-amino-5-phosphonovalerate. Other compounds which produce stereotyped behavior in vivo also inhibited the NMDA-stimulated flux of 22Na and the rank of the percentage inhibition of the NMDA-stimulated flux correlated with the affinities at the phencyclidine receptor with 97% confidence. The structural diversity and selectivity for the phencyclidine receptor of those compounds which inhibited the NMDA-stimulated flux of 22Na argue that the interaction was at the phencyclidine receptor. The presence of magnesium did not alter the relative magnitude of inhibition by phencyclidine, suggesting that the phencyclidine site is separate from the pressumably, channel-blocking magnesium site. Thus, the data of the present study support a model where the phencyclidine site is separate from the NMDA recognition site and from the presumed channel-blocking site of magnesium within the NMDA-associated ion channel.