1-Aminocyclopropanecarboxylic acid is a high affinity ligand with partial agonist properties at strychnine-insensitive glycine sites associated with the N-methyl-D-aspartate subtype of glutamate receptors. Since occupation of these sites appears required for operation of N-methyl-D-aspartate, receptor coupled cation channels, it was hypothesized that a glycine partial agonist could function as an N-methyl-D-aspartate antagonist. This hypothesis was examined by evaluating the in vivo and in vitro neuroprotective actions of 1-aminocyclopropanecarboxylic acid. 1-Aminocyclopropanecarboxlic acid (150-600 mg kg-1) administered to gerbils five minutes following twenty minutes of forebrain ischemia significantly improved seven day survival; the optimal dose (300 mg kg-1) increased 7 days survival > 4-fold, from 20% to 92%. Survival of hippocampal CA1 neurons (quantitated 7 days post-ischemia) was significantly (approximately 3-fold) increased by the 600 mg kg-1 dose. Seven day survival was not significantly increased when the interval between reperfusion and drug administration (300 mg kg-1) was increased from 5 to 30 min. In cerebellar granule cell cultures, NMDA combined with a saturating concentration of glycine (10 microM) resulted in a 500% increase in cGMP levels. cGMP levels were increased by 100% over basal when NMDA was combined with a saturating (10 microM) concentration of ACPC, indicating that in this measure, the efficacy of ACPC relative to glycine was approximately 0.2. Consistent with previous findings, 1-aminocyclopropanecarboxylic acid significantly reduced glutamate-induced neurotoxicity in cerebellar granule cell cultures. ACPC was most effective in blocking neurotoxicity at glutamate concentrations producing low to moderate levels of cell death.(ABSTRACT TRUNCATED AT 250 WORDS)