Psychopharmacology

, Volume 102, Issue 4, pp 551–552 | Cite as

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

  • Christian Chiamulera
  • Silvano Costa
  • Angelo Reggiani
Rapid Communications

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.

Key words

NMDA receptor antagonists Glycine antagonists Convulsions Learning 

References

  1. Johnson A, Ascher P (1987) Glycine potentiates the NMDA responses in cultured mouse brain neurons. Nature 325:529–531CrossRefPubMedGoogle Scholar
  2. Koek W, Colpaert FC (1990) Selective blockade of N-methyl-d-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther 252:349–357PubMedGoogle Scholar
  3. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113Google Scholar
  4. Lodge D (1988) Excitatory amino acids in health and disease. Wiley, ChichesterGoogle Scholar
  5. Lodge D, Johnson KM (1990) Noncompetitive excitatory amino acid receptor antagonists. TIPS 11:81–86PubMedGoogle Scholar
  6. Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-antagonist, AP5. Nature 319:774–776Google Scholar
  7. Turski L, Meldrum BS, Collins JF (1985) Anticonvulsant action of beta-kainic acid in mice. Is beta-kainic acid an N-methyl-d-aspartate antagonist? Brain Res 336:162–166CrossRefPubMedGoogle Scholar
  8. Watkins JC, Krosgaard-Larsen P, Honoré T (1990) Structure-activity relationship in the development of excitatory amino acid receptor agonists and competitive antagonists. TIPS 11:25–33PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Christian Chiamulera
    • 1
  • Silvano Costa
    • 1
  • Angelo Reggiani
    • 1
  1. 1.Glaxo Research LaboratoriesVeronaItaly

Personalised recommendations