EFFECTS OF IONOTROPIC EXCITATORY AMINO-ACID RECEPTOR ANTAGONISTS ON GLUTAMATE TRANSPORT AND TRANSPORT-MEDIATED CHANGES IN EXTRACELLULAR EXCITATORY AMINO-ACIDS IN THE RAT STRIATUM

This study examined the effects of intrastriatal administration of ion otropic excitatory amino acid receptor antagonists on biochemical mark ers of excitatory amino acid transmission in the rat striatum. High-af finity glutamate uptake was measured ex vivo on striatal homogenates 1 5 min after the local administration of either 6,7-dinitroquinoxaline- 2,3-dione (DNQX), a non-NMDA receptor antagonist, or DL-2-amino-5-phos phonopentanoic acid (AP5), a competitive NMDA antagonist, at various d oses (10-500 pmol injected). DNQX induced a dose-dependent increase in glutamate uptake rate, related to an increase in the V-max of the tra nsport process, whereas no significant change in glutamate uptake was detected after AP5 administration. Similar results were obtained from animals subjected to excitotoxic lesion of striatal neurons by kainate administration 15 days before the injection of DNQX or AP5. In a para llel series of experiments using in vivo microdialysis we showed that DNQX (10(-5) M) in the dialysis probe diminished by similar to 30-40% the increases in the concentrations of glutamate and aspartate elicite d by L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM). These data sugg est that presynaptic glutamate transmission in the rat striatum may un dergo facilitatory autoregulatory processes involving ionotropic non-N MDA receptors and highlight the view that transporters for glutamate m ay be potent regulatory sites for glutamatergic transmission.