The NMDA receptor agonist DL-(tetrazol-5-yl) glycine is a highly potent excitotoxin

Darryle D. Schoepp, William H.W. Lunn, Craig R. Salhoff, John W. McDonald

Research output: Contribution to journalArticlepeer-review

Abstract

DL-(Tetrazol-5-yl)glycine is a highly selective N-methyl-D-aspartate (NMDA) receptor agonist with nanomolar in vitro potency. Previous work showed that DL-(tetrazol-5-yl)glycine has greater affinity and efficacy at NMDA receptors than other NMDA receptor agonists such as cis-methanoglutamate and NMDA. In this study, the in vivo excitotoxic potency of DL-(tetrazol-5-yl)glycine was compared to cis-methanoglutamate and NMDA. Adult (250-300 g) and neonatal (7-day-old) rats were anesthetized and compounds were unilaterally injected into the striatum. In adult rats DL-(tetrazol-5-yl)glycine (0.3-1.0 nmol/μl) produced highly significant losses of striatal γ-aminobutyric acid neurons (as indexed by glutamic acid decarboxylase activity) and cholinergic neurons (as indexed by choline acetyltransferase activity). Dose-response showed that DL-(tetrazol-5-yl)glycine was about 100 and 500 times more potent than cis-methanoglutamate and NMDA, respectively. In neonatal rats, DL-(tetrazol-5-yl)glycine (0.1-0.3 nmol/μl) produced significant brain damage as indicated by brain weight losses 5 days later. DL-(Tetrazol-5-yl)glycine was about 50 and 150 times more potent than cis-methanoglutamate and NMDA, respectively, in the neonate. The excitotoxic potency of DL-(tetrazol-5-yl)glycine is likely due to its greater efficacy and potency at the NMDA receptor, when compared to other NMDA receptor agonists. The remarkable in vivo potency of DL-(tetrazol-5-yl)glycine in producing excitotoxic lesions makes it a useful agent to further probe NMDA receptor mediated ecitotoxicity in brain pathologies.

Original languageEnglish (US)
Pages (from-to)67-72
Number of pages6
JournalEuropean Journal of Pharmacology: Environmental Toxicology and
Volume270
Issue number1
DOIs
StatePublished - Jan 3 1994

Keywords

  • DL-(Tetrazol-5-yl)glycine
  • Excitotoxicity
  • NMDA (N-methyl-D-aspartate)
  • Neurodegeneration
  • cis-Methanoglutamate

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Pollution

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