Effect of NMDA- and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning

Abstract

Intracerebroventricular (ICV) injection of N-methyl-d-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonistsdl-2-amino-5-phosphonovaleroate (dl-AP7) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), the NMDA “channel blocker” antagonist (+)-5-methyl-10,11-dihydro 5H-dibenzo-[a,d] cycloheptan-5,10-imine maleate (MK-801) and the strychnine-insensitive glycine antagonists kynurenic acid (KYNA) and 7-chloro-kynurenic acid (7-Cl-KYNA), when co-administered (ICV) with NMDA, antagonized NMDA-induced generalized seizures. Administration (ICV) ofdl-AP7, CPP and MK-801 resulted in impared learning performance in a passive avoidance task in mice, with ED₅₀ close to the anticonvulsant dose. The glycine antagonists KYNA and 7-Cl-KYNA at high doses significantly failed to affect performance in the same model of learning. The results indicate that compounds acting at the strychnine-insensitive glycine site may have a larger “therapeutic window” as anticonvulsants than antagonists of the NMDA receptor and channel.