Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors

Abstract

Oxiracetam, aniracetam and d-cycloserine, three putative cognition enhancers, were examined in a functional assay for NMDA receptors. Rat hippocampal slices or synaptosomes were labeled with [ 3H]noradrenaline and exposed to NMDA or glutamate in superfusion. NMDA (100 μM) elicited a remarkable rise (about 500%) in the release of [ 3H]noradrenaline from slices. The effect of NMDA was antagonized by the glutamate receptor blocker, kynurenic acid. The antagonism by 100 μM kynurenate was reduced by submicromolar concentrations of oxiracetam and totally reversed by 1 μM of the drug. The concentration-antagonism curve for kynurenic acid was shifted to the right in the presence of 0.2 or 1 μM oxiracetam. Aniracetam and d-cycloserine, as well as glycine and d-serine, behaved similarly to oxiracetam: all compounds, tested at 1 μM, reversed the antagonism by 100 μM kynurenate of the NMDA-evoked [ 3H]noradrenaline release. In superfused hippocampal synaptosomes, 100 μM NMDA or glutamic acid elicited the release of [ 3H]noradrenaline; the evoked release was enhanced by glycine, but not by oxiracetam. In this preparation 1 μM glycine or 1 μM oxiracetam prevented the antagonism by kynurenate of the NMDA- or the glutamate-evoked [ 3H]noradrenaline release. As kynurenic acid is an endogenous glutamate receptor antagonist whose brain levels are known to increase in conditions associated to cognitive deficits, it is proposed that the putative cognition enhancers tested may act in vivo by relieving the antagonism produced by excessive endogenous kynurenate.