The glutamate transporter inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) reversibly enhanced hippocampal neuronal activity in the rat and mouse dentate gyrus. The PDC action was still found in mice lacking the glial glutamate transporter GLT-1. PDC did not influence the rate of spontaneous miniature excitatory postsynaptic Currents and spontaneous inhibitory postsynaptic currents, ionotropic glutamate receptor currents, or GABA-evoked currents in cultured rat hippocampal neurons. PDC increased glutamate released from Cultured hippocampal astrocytes from normal rats, normal mice. and GLT-1 knock-out mice, that is not inhibited by deleting extracellular Na+, while the drug had no effect on the release from cultured rat hippocampal neurons. The results of the present study thus Suggest that PDC stimulates glial glutamate release by a mechanism independent of inhibiting glutamate transporters, which perhaps Causes an increase in synaptic glutamate concentrations, in part responsible for the enhancement in hippocampal neuronal activity. (C) 2002 Elsevier Science (USA). All rights reserved.