Kynurenine and glycine enhance neuronal sensitivity to N-methyl-D-aspartate

Neurones in rat hippocampal slices were excited by microiontophoretic applications of N-methyl-D-aspartate (NMDA) and kainate. Responses to NMDA were potentiated by glycine 300 microM or 1 mM in the perfusing medium. A small potentiation of kainate was not observed in the presence of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (2AP5). The potentiation of NMDA responses by glycine was not prevented by strychnine 5 or 30 microM and was also shown by D-serine and L-kynurenine but not L-leucine. If sensitivity to NMDA was reduced by kynurenic acid, glycine and L-kynurenine produced a greater enhancement of NMDA. The requirement of NMDA receptor activation for the occupation of strychnine-resistant glycine sites can thus be demonstrated in complex systems such as brain slices. It is possible that L-kynurenine may also be an endogenous ligand capable of modulating NMDA sensitivity.