REGULATION OF N-METHYL-D-ASPARTATE-INDUCED TOXICITY IN THE NEOSTRIATUM - A ROLE FOR METABOTROPIC GLUTAMATE RECEPTORS

Glutamate release activates multiple receptors that interact with each other and thus determine the response of the cell. Exploring these in teractions is critical to developing an understanding of the functiona l consequences of synaptic transmission. Activation of metabotropic gl utamate receptors (mGluRs) inhibits N-methyl-D-aspartate (NMDA)-evoked responses measured electrophysiologically in neostriatal slices. The present study examines the functional consequences of this regulation using infrared differential interference contrast videomicroscopy to m easure and characterize glutamate receptor-induced cell swelling in a neostriatal brain slice preparation, This swelling is, In many cases, a prelude to necrotic cell death and the dye trypan blue was used to c onfirm that swelling can result in the death of neostriatal cells, Act ivation of mGluRs by the agonist 1-aminocyclopentane-1,3-dicarboxylic acid (tACPD) inhibited NMDA but not amino-3-hydroxy-5-methyl-4-isoxazo lepropionic acid/kainate-induced swelling. This regulation was cell-ty pe specific as tACPD did not alter NMDA-induced swelling In pyramidal cells of the hippocampus. Importantly, these findings could be extende d to in vivo preparations, Pretreatment with tACPD limited the size of lesions and associated behavioral deficits induced by intrastriatal a dministration of the NMDA receptor agonist quinolinic acid.