L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked striatal glutamate levels are attenuated by calcium reduction, tetrodotoxin, and glutamate receptor blockade.

L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) reverses plasma membrane glutamate transporters and elevates extracellular glutamate levels in vivo. We investigated the possibility that L-trans-PDC-stimulated glutamate levels are mediated partially by increases in transsynaptic activity. Therefore, the degree to which L-trans-PDC-evoked glutamate levels depend on calcium, sodium-channel activation, and glutamate-receptor activation was investigated by infusing via reverse microdialysis (a) 0.1 mM calcium, (b) 1 microM tetrodotoxin, a selective blocker of voltage-dependent sodium channels, (c) R(-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a selective NMDA-receptor antagonist, or (d) LY293558, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist. In separate experimental groups, L-trans-PDC-evoked glutamate levels were reduced significantly by 55% in the presence of 0.1 mM calcium and by 46% in the presence of tetrodotoxin. Additionally, CPP and LY293558 significantly attenuated L-trans-PDC-evoked glutamate levels without altering basal glutamate levels. These data suggest that glutamate transporter reversal by L-trans-PDC initially elevates extracellular glutamate levels enough to stimulate postsynaptic glutamate receptors within the striatum. It is proposed that glutamate-receptor stimulation activates a positive feedback loop within the basal ganglia, leading to further glutamate release from corticostriatal and thalamostriatal afferents. Therefore, either extracellular striatal calcium reduction or tetrodotoxin perfusion leads to decreased action potential-dependent glutamate release from these terminals. In addition, blocking glutamate receptors directly reduces medium spiny neuronal firing and indirectly attenuates corticostriatal and thalamostriatal activity, resulting in an overall depression of L-trans-PDC-stimulated glutamate levels.