Abstract

Some putative cognition enhancers (oxiracetam, aniracetam andd-cycloserine) 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≃ 0.1 μM) prevented the kynurenate (100 μM) block of the NMDA (100 μM)-evoked [³H]NE release. l-Serine was ineffective up to 10 μM. The γ-aminobutyric acid_B (GABA_B) receptor antagonist CGP 36742, reported to improve cognitive performance, potently prevented the kynurenate antagonism. The activity of CGP 36742 (1 μM) appeared to be unaffected by 10 μM (−)-baclofen, a GABA_B receptor agonist; furthermore, CGP 52432, a GABA_B antagonist more potent than CGP 36742, but reportedly devoid of nootropic properties, was inactive in the “kynurenate test.” The novel putative cognition enhancer CR2249, but not its enantiomer CR2361, also potently prevented the kynurenate antagonism. In contrast, linopirdine, nicotine and tacrine were inactive. In rat hippocampal synaptosomes glycine and d-cycloserine enhanced the NMDA-evoked [³H]NE release, whereas oxiracetam and CR2249 did not. These four compounds were all similarly effective in preventing kynurenate antagonism, both in slices and in synaptosomes. The NMDA potentiation caused by glycine (0.1–100 μM) was not affected by 100 μM 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 anin vitro assay useful in the identification and characterization of putative cognition enhancers actingvia NMDA receptors.