Effects of N-methyl-D-aspartate, kainate or veratridine on extracellular concentrations of free D-serine and L-glutamate in rat striatum: an in vivo microdialysis study.

Using an in vivo microdialysis technique, we have investigated the effect of N-methyl-D-aspartate (NMDA) or kainate on the extracellular concentrations of free D-serine and L-glutamate in the striatum. A intrastriatal perfusion of NMDA or kainate caused a significant increase in the extracellular release of L-glutamate, but a significant decrease in that of D-serine. Co-perfusion of an NMDA receptor antagonist, MK-801, or an alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), with NMDA or kainate significantly reversed the NMDA- or kainate-induced decrease in the extracellular level of D-serine, respectively. The NMDA- or kainate-evoked increase in the extracellular L-glutamate level was also reversed by co-perfusion of MK-801 or CNQX, respectively. Because D-serine acts as a potent and selective agonist for the glycine site of the NMDA receptor and because intracerebroventricularly injected D-serine is accumulated in the astrocytes, D-serine could be taken up by the astrocytes following synaptic activation. Furthermore, because cortical ablation to remove corticostriatal glutamatergic inputs attenuates the excitotoxic effects of kainate in the striatum, L-glutamate may enhance its own release through a presynaptic NMDA and/or non-NMDA receptor-mediated mechanism.