Effect of NMDA- and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning.
Intracerebroventricular (ICV) injection of N-methyl-D-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonists DL-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) of DL-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.
Chiamulera
C
C
Glaxo Research Laboratories, Verona, Italy.
Costa
S
S
Reggiani
A
A
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007276:Injections, Intraventricular; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced*; D013331:Strychnine / Q000494:pharmacology*
D010879:Piperazines; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007736:Kynurenic Acid; D013331:Strychnine; C057013:7-chlorokynurenic acid