EXTRACELLULAR CONCENTRATION OF ENDOGENOUS FREE D-SERINE IN THE RAT-BRAIN AS REVEALED BY IN-VIVO MICRODIALYSIS

Using an in vivo microdialysis technique, we have measured the extracellular concentration of endogenous free D-serine in comparison with that of L-serine, glycine and L-glutamate in the discrete brain areas of the freely moving rat. A high concentration of D-serine was observed in the dialysate obtained from the medial prefrontal cortex and striatum, whereas the cerebellar dialysate contained only a trace amount of the D-amino acid. The regional variation in the basal overflow of D-serine was proportional to that of its tissue levels which has been shown to closely correlate with the distribution of the N-methyl-D-aspartate type excitatory amino acid receptor. In contrast, the extracellular release of glycine and L-glutamate was higher in the cerebellum and very low in the striatum. The extracellular concentrations of L-serine were more than three times those of striatal D-serine in the three regions. Neither addition of a sodium channel blocker, tetrodotoxin (2 mu M), nor deprivation of Ca2+ from the perfusate reduced the basal extracellular levels of the four amino acids tested in the medial prefrontal cortex. Furthermore, intra-frontal cortex perfusion of a sodium channel activator, veratrine (200 mu g/ml), caused an increase in the extracellular release of glycine and L-glutamate but a slight decrease in that of D-serine in a tetrodotoxin-sensitive manner in the cortical region. Because D-serine is known to act as a selective agonist for the glycine modulatory site of the N-methyl-D-asparate receptor, the presence of extracellular D-serine release and its distribution profile in the brain further support the view that D-serine as well as glycine may be endogenous modulators of brain N-methyl-D-aspartate receptors. The tetrodotoxin- and Ca2+-deprivation-resistant nature and the lack of veratrine-induced increase suggest that D-serine might be liberated into the extracellular space from non-neuronal cells or certain exceptional neuronal cells probably by a carrier-mediated process.