GLYCINE SITE ANTAGONISTS AND PARTIAL AGONISTS INHIBIT N-METHYL-D-ASPARTATE RECEPTOR-MEDIATED [H-3]ARACHIDONIC ACID RELEASE IN CEREBELLAR GRANULE CELLS

Activation of N-methyl-D-aspartate (NMDA) receptors is known to produc e arachidonic acid release, which has been implicated in excitotoxicit y. Antagonists and partial agonists at the glycine site of the NMDA re ceptor, despite exhibiting functional differences in electrophysiologi cal studies, inhibit glutamate-induced neurotoxicity and ischemia-indu ced neurodegeneration. The objective of this study was to investigate the effects of both glycine site antagonists and partial agonists on N MDA receptor-mediated [H-3]arachidonic acid (AA) release evoked by glu tamate, NMDA or a competitive inhibitor of the glutamate/aspartate upt ake carrier. The [H-3]AA release evoked by a maximally effective conce ntration of glutamate (100 mu M) was blocked by the glycine site antag onists 7-chlorokynurenic acid (7-CKYN) and 5,7-dichlorokynurenic acid (5,7-DCKYN) and by a low intrinsic efficacy glycine partial agonist ()-1-hydroxy-3-aminopyrrolid-2-one [(+)-HA-966], 1-Aminocyclopropanecar boxylic acid (ACPC), a high intrinsic efficacy glycine partial agonist , did not modify [H-3]AA release evoked by 100 mu M glutamate. However , ACPC blocked (in a glycine reversible manner) the [H-3]AA release in duced by NMDA (100 mu M) with an IC50 of 131 +/- 2 mu M. Furthermore, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a competitive inhibitor o f the glutamate transporter, also released [H-3]AA (E-max and EC50 of 127 +/- 4% and 30 +/- 1 mu M, respectively). ACPC, 7-CKYN and (+)-2-am ino-7-phosphonoheptanoic acid (AP-7), a competitive NMDA receptor anta gonist, inhibited [H-3]AA release evoked by PDC. These results demonst rate that both glycine site antagonists and partial agonists can inhib it NMDA receptor-mediated [H-3]AA release in cerebellar granule cells, an action consistent with the neuroprotective effects of these compou nds.