L-ALPHA-AMINOADIPIC ACID AS A REGULATOR OF KYNURENIC ACID PRODUCTION IN THE HIPPOCAMPUS - A MICRODIALYSIS STUDY IN FREELY MOVING RATS

L-alpha-Aminoadipic acid is a lysine metabolite with neuroexcitatory p roperties, and has previously been shown to inhibit the production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid in brain tissue slices. The effects of L-alpha-aminoadipic acid on the levels of extracellular kynurenic acid were now studied by micr odialysis in the dorsal hippocampus of freely moving rats. Application of L-alpha-aminoadipic acid through the microdialysis probe dose depe ndently decreased both the concentration of endogenous kynurenic acid and of kynurenic acid which was produced de novo from its bioprecursor L-kynurenine (500 mu M applied through the probe). 500 mu M L-alpha-a minoadipic acid lowered the kynurenic acid concentration in the dialys ate by 47% and 28% with and without precursor loading, respectively, w hereas D-alpha-aminoadipic acid was without effect. Co-administration of 500 mu M L-alpha-aminoadipic acid with 50 mu M veratridine, which b y itself produces a substantial decrease in the levels of extracellula r kynurenic acid, did not result in a further reduction in kynurenic a cid concentrations. Extensive neuronal degeneration caused by an intra hippocampal injection of quinolinic acid (120 nmol) did not interfere with the effect of L-alpha-aminoadipic acid. Taken together, these dat a suggest that the effect of L-alpha-aminoadipic acid on extracellular kynurenic acid levels is likely due to its direct action on astrocyte s, which are known to harbor kynurenic acid's biosynthetic enzyme, kyn urenine aminotransferase. L-alpha-Aminoadipic acid may modulate kynure nic acid function in the brain and thus play a role in the pathogenesi s of neurodegenerative and seizure disorders.