PUTATIVE COGNITION ENHANCERS REVERSE KYNURENIC ACID ANTAGONISM AT HIPPOCAMPAL NMDA RECEPTORS

Oxiracetam, aniracetam and D-cycloserine, three putative cognition enh ancers, were examined in a functional assay for NMDA receptors. Rat hi ppocampal slices or synaptosomes were labeled with [H-3]noradrenaline and exposed to NMDA or glutamate in superfusion. NMDA (100 mu M) elici ted a remarkable rise (about 500%) in the release of [H-3]noradrenalin e from slices. The effect of NMDA was antagonized by the glutamate rec eptor blocker, kynurenic acid. The antagonism by 100 mu M kynurenate w as reduced by submicromolar concentrations of oxiracetam and totally r eversed by 1 mu M of the drug. The concentration-antagonism curve for kynurenic acid was shifted to the right in the presence of 0.2 or 1 mu M oxiracetam. Aniracetam and D-cycloserine, as well as glycine and D- serine, behaved similarly to oxiracetam: all compounds, tested at 1 mu M, reversed the antagonism by 100 mu M kynurenate of the NMDA-evoked [H-3]noradrenaline release. In superfused hippocampal synaptosomes, 10 0 mu M NMDA or glutamic acid elicited the release of [H-3]noradrenalin e; the evoked release was enhanced by glycine, but not by oxiracetam. In this preparation 1 mu M glycine or 1 mu M oxiracetam prevented the antagonism by kynurenate of the NMDA- or the glutamate-evoked [H-3]nor adrenaline release. As kynurenic acid is an endogenous glutamate recep tor antagonist whose brain levels are known to increase in conditions associated to cognitive deficits, it is proposed that the putative cog nition enhancers tested may act in vivo by relieving the antagonism pr oduced by excessive endogenous kynurenate.