THE KYNURENATE TEST, A BIOCHEMICAL ASSAY FOR PUTATIVE COGNITION ENHANCERS

Some putative cognition enhancers (oxiracetam, aniracetam and D-cyclos erine) were previously shown to prevent the kynurenic acid antagonism of the N-methyl-D-aspartate (NMDA)-evoked norepinephrine (NE) release in rat hippocampal slices. This functional in vitro assay was further characterized in the present work. D-Serine, a glutamate coagonist at the NMDA receptor glycine site, concentration-dependently (EC50 simila r or equal to 0.1 mu M) prevented the kynurenate (100 mu M) block of t he NMDA (100 mu M)-evoked [H-3]NE release. L-Serine was ineffective up to 10 mu M. The gamma-aminobutyric acid(B) (GABA(B)) receptor antagon ist CGP 36742, reported to improve cognitive performance, potently pre vented the kynurenate antagonism. The activity of CGP 36742 (1 mu M) a ppeared to be unaffected by 10 mu M (-)-baclofen, a GABA(B) receptor a gonist; furthermore, CGP 52432, a GABA(B) antagonist more potent than CGP 36742, but reportedly devoid of nootrapic properties, was inactive in the ''kynurenate test.'' The novel putative cognition enhancer CR2 249, but not its enantiomer CR2361, also potently prevented the kynure nate antagonism. In contrast, linopirdine, nicotine and tacrine were i nactive. In rat hippocampal synaptosomes glycine and D-cycloserine enh anced the NMDA-evoked [H-3]NE release, whereas oxiracetam and CR2249 d id not. These four compounds were ail similarly effective in preventin g kynurenate antagonism, both in slices and in synaptosomes. The NMDA potentiation caused by glycine (0.1-100 mu M) was not affected by 100 mu M oxiracetam, which suggested that drugs active in the ''kynurenate test'' may bind to sites different from the glycine site of the NMDA receptor. To conclude, the ''kynurenate test'' is an in vitro assay us eful in the identification and characterization of putative cognition enhancers acting via NMDA receptors.