EFFECTS OF CENTRAL AND PERIPHERAL ADMINISTRATION OF KYNURENIC ACID ONHIPPOCAMPAL EVOKED-RESPONSES IN-VIVO AND IN-VITRO

Kynurenic acid is an excitatory amino acid antagonist with preferentia l activity at the N-methyl-D-aspartate subtype of glutamate receptors. It is produced endogenously in the brain, but is synthesized more eff ectively in the periphery. The influence of peripheral kynurenic acid on brain function is unclear because kynurenic acid is likely to penet rate the blood-brain barrier poorly. To determine the potential centra l effects of peripheral kynurenic acid, we compared its effects in the hippocampus after peripheral or direct administration. The hippocampu s of the rat was chosen at: a test system because this region receives glutamatergic inputs, and because responses to stimulation of these i nputs can be compared after peripheral drug administration in vivo, an d after direct administration of drugs in vivo. Peripherally-administe red kynurenic acid was injected via a catheter in the jugular vein. Ba th-application to hippocampal slices was used to test effects of direc t administration. Area CAI pyramidal cells and dentate gyrus granule c ells were examined by extracellular recording and stimulation of area CA3 or the perforant path, respectively. Pairs of identical stimuli we re used to assess paired-pulse inhibition and paired-pulse facilitatio n. Kynurenic acid decreased evoked responses in area CA1 and the denta te gyrus, both ii? vivo and in vitro. Effective concentrations were in the low micromolar range, and therefore were likely to be mediated by antagonism of N-methyl-D-aspartate receptors. In both preparations, a rea CA1 was more sensitive than the dentate gyrus, and paired-pulse fa cilitation was affected, but not paired-pulse inhibition. Control solu tions had no effect. We conclude that kynurenic acid can enter the bra in after peripheral administration, and that peripheral and direct eff ects in the hippocampus are qualitatively similar. Therefore, we predi ct that effects of endogenous kynurenic acid that was synthesized peri pherally or centrally would be similar. Furthermore, the results sugge st that modulation of the glycine site of the N-methyl-D-aspartate rec eptor, for example by kynurenic acid, may vary considerably among diff erent brain areas. (C) 1998 IBRO. Published by Elsevier Science Ltd.