Regulation of kynurenic acid synthesis studied by microdialysis in the dorsal hippocampus of unanesthetized rats.
The production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid was assessed by hippocampal microdialysis in freely moving rats. Extracellular kynurenic acid, determined spectrophotometrically, was measured following the perfusion of its bioprecursor L-kynurenine (500 microM) through the dialysis probe. In this paradigm, the concentration of kynurenic acid reached plateau levels within 2 h. These steady state levels were more than doubled in gliotic quinolinate-lesioned tissue. The non-specific inhibitor of kynurenine aminotransferase, aminooxyacetic acid (300 microM), and the depolarizing agent veratridine (50 microM), introduced through the dialysis membrane, caused a 69 and 57% decrease, respectively, in extracellular kynurenic acid. The effect of veratridine was rapidly reversible and was blocked by 5 microM tetrodotoxin or in the quinolinate-lesioned hippocampus. In contrast, the effect of aminooxyacetic acid was longer lasting upon drug discontinuation, and was not reversed by tetrodotoxin or in lesioned tissue. These data demonstrate that hippocampal kynurenic acid can be regulated by direct interference with its biosynthetic enzyme and by a distinct process involving neuron-glia interactions.
Wu
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HQ
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Ungerstedt
U
U
Schwarcz
R
R
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism; D003956:Dialysis / Q000379:methods; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D017378:Quinolinic Acid; D011805:Quinolinic Acids; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D011805:Quinolinic Acids; D000625:Aminooxyacetic Acid; D007737:Kynurenine; D013779:Tetrodotoxin; D014701:Veratridine; D017378:Quinolinic Acid; D007736:Kynurenic Acid