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

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/microliters) produced highly significant losses of striatal gamma-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/microliters) 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 excitotoxicity in brain pathologies.