Effect of NMDA- And Strychnine-Insensitive Glycine Site Antagonists on NMDA-mediated Convulsions and Learning

Psychopharmacology (Berl). 1990;102(4):551-2. doi: 10.1007/BF02247140.

Abstract

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.

MeSH terms

  • 2-Amino-5-phosphonovalerate / analogs & derivatives
  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Dizocilpine Maleate / pharmacology
  • Injections, Intraventricular
  • Kynurenic Acid / analogs & derivatives
  • Kynurenic Acid / pharmacology
  • Learning / drug effects*
  • Male
  • Mice
  • N-Methylaspartate / antagonists & inhibitors
  • N-Methylaspartate / pharmacology*
  • Piperazines / pharmacology
  • Receptors, Glycine
  • Receptors, Neurotransmitter / drug effects*
  • Seizures / chemically induced*
  • Strychnine / pharmacology*

Substances

  • Piperazines
  • Receptors, Glycine
  • Receptors, Neurotransmitter
  • 2-amino-4-methyl-5-phosphono-3-pentenoic acid
  • N-Methylaspartate
  • Dizocilpine Maleate
  • 2-Amino-5-phosphonovalerate
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • Kynurenic Acid
  • Strychnine
  • 7-chlorokynurenic acid