Glycine site antagonists and partial agonists inhibit N-methyl-D-aspartate receptor-mediated

ABSTRACT Activation of N-methyl-D-aspartate (NMDA) receptors is known to produce arachidonic acid release, which has been implicated in excitotoxicity. Antagonists and partial agonists at the glycine site of the NMDA receptor, despite exhibiting functional differences in electrophysiological studies, inhibit glutamateinduced neurotoxicity and ischemia-induced neurodegeneration. The objective of this study was to investigate the effects of both glycine site antagonists and partial agonists on NMDA receptor-mediated [ 3 H]arachidonic acid (AA) release evoked by glutamate, NMDA or a competitive inhibitor of the glutamate/ aspartate uptake carrier. The [ 3 H]AA release evoked by a maximally effective concentration of glutamate (100 M) was blocked by the glycine site antagonists 7-chlorokynurenic acid (7-CKYN) and 5,7-dichlorokynurenic acid (5,7-DCKYN) and by a low intrinsic efficacy glycine partial agonist (ϩ)-1-hydroxy-3-aminopyrrolid-2-one [(ϩ)-HA-966]