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 efficac y at NMDA receptors than other NMDA receptor agonists such as cis-meth anoglutamate 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 anesthetize d and compounds were unilaterally injected into the striatum. In adult rats DL-(tetrazol-5-yl)glycine (0.3-1.0 nmol/mu l) produced highly si gnificant losses of striatal <gamma-aminobutyric acid neurons (as inde xed by glutamic acid decarboxylase activity) and cholinergic neurons ( as indexed by choline acetyltransferase activity). Dose-response showe d that DL-(tetrazol-5-yl)glycine was about 100 and 500 times more pote nt than cis-methanoglutamate and NMDA, respectively. In neonatal rats, DL-(tetrazol-5-yl)glycine (0.1-0.3 nmol/mu l) produced significant br ain damage as indicated by brain weight losses 5 days later. DL-(Tetra zol-5-yl)glycine was about 50 and 150 times more potent than cis-metha noglutamate and NMDA, respectively, in the neonate. The excitotoxic po tency of DL-(tetrazol-5-yl)glycine is likely due to its greater effica cy and potency at the NMDA receptor, when compared to other NMDA recep tor agonists. The remarkable in vivo potency of DL-(tetrazol-5-yl)glyc ine in producing excitotoxic lesions makes it a useful agent to furthe r probe NMDA receptor mediated excitotoxicity in brain pathologies.