RAPID DESENSITIZATION DETERMINES THE PHARMACOLOGY OF GLUTAMATE NEUROTOXICITY

Glutamate (Glu), the major excitatory neurotransmitter in the nervous system, is toxic to neurons when it accumulates at high concentrations in the extracellular space. Even though Glu is a mixed agonist, capab le of activating N-methyl-D-aspartate (NMDA) receptors and non-NMDA re ceptors, in many preparations Glu neurotoxicity is prevented by select ive blockade of NMDA receptors. In cultures of hippocampal neurons, tr eatment with 500 mu M Glu for 30 min killed more than 90% of the neuro ns. The simultaneous addition of the selective NMDA agonist yl-10,11-d ihydro-5-H-dibenzocyclohepten-5,10-imine (MK-801) reduced the cell los s to less than 30%. However, when Glu was combined with either diazoxi de or cyclothiazide, two thiazides which dramatically diminish rapid G lu desensitization, MK-801 was no longer very protective and neuronal loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroqui noxaline-2,3-dione (CNQX), in combination with MK-801, was able to pre vent most Glu neurotoxicity in the presence of these thiazides. These experiments show that there are circumstances under which Glu neurotox icity is produced by overactivation of non-NMDA receptors. Our observa tions offer a possible explanation for the recent finding that blockad e of non-NMDA receptors is much more beneficial than NMDA receptor blo ckade in protecting the brain in some in vivo models of global ischemi a.