KAINATE EXCITOTOXICITY IS MEDIATED BY AMPA-PREFERRING BUT NOT KAINATE-PREFERRING RECEPTORS IN EMBRYONIC RAT HIPPOCAMPAL CULTURES

We investigated kainate-induced excitotoxicity in embryonic rat hippoc ampal cells cultured in a chemically defined medium. Treatment with ka inate for 24 h resulted in neuronal death, as assessed by the release of lactate dehydrogenase into the culture media. This neurotoxic effec t was kainate dose-and culture age-dependent. EC50 of kainate was 127 +/- 11 mu M. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinoxaline (NB QX) completely blocked the toxicity, while MK801, an N-methyl-D-aspart ate (NMDA) receptor antagonist, also blocked it but not completely. Fu rthermore, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ( AMPA) attenuated the kainate injury, while the selective and noncompet itive AMPA-preferring receptor antagonist 1-(4-aminophenyl)-4-methyl-7 ,8-methylene diazepine (GYKI 52466) blocked it completely. Concanavali n A (ConA), which potentiates the response to kainate at kainate-prefe rring receptors, had little effect on kainate toxicity. Further, AMPA alone induced little toxicity, but produced remarkable toxicity when c yclothazide was used to block the desensitization of AMPA-preferring r eceptors. These results indicate that kainate excitotoxicity in hippoc ampal cultures is mediated by AMPA- but not kainate-preferring recepto rs, and that it involves NMDA receptor-mediated toxicity. The non-dese nsitizing response at AMPA-preferring receptors may play an important role in kainate-induced excitotoxicity. (C) 1997 Elsevier Science Ltd.