Both acute and chronic treatments with the glycine partial agonist 1-aminocyclopropanecarboxylic acid (ACPC) are neuroprotective in animal models of focal, global and spinal ischemia. After a chronic regimen of ACPC, brain and plasma levels were undetectable at the time of ischemic insult, which suggests that the neuroprotective effects of acute and chronic ACPC are mediated by different mechanisms. To investigate the possibility that chronic administration of ACPC alters N-methyl-D-aspartate (NMDA) receptor composition, the levels of mRNAs encoding zeta and epsilon subunits were quantified by in situ hybridization histochemistry with 35S-labeled riboprobes. Chronic ACPC administered to mice (200 mg/kg for 14 days) increased the level of epsilon-1 mRNA in the hippocampus (particularly CA1 and CA2 regions) and cerebral cortex (frontal, parietal and occipital regions), without altering levels in cerebellum. In contrast, this regimen decreased epsilon-3 subunit mRNA levels in the hippocampus (especially CA1 and dentate gyrus) and frontal and occipital cortices. Decreases in epsilon-2 subunit mRNA levels in cerebral cortex (especially frontal and parietal cortices) were also observed without accompanying alterations in the cerebellum, hippocampus or dentate gyrus. The levels of zeta subunit mRNA (determined with a probe that detects all splice variants) were not altered in any brain areas examined. Based on studies in recombinant receptors, these region-specific changes in mRNAs produced by a chronic regimen of ACPC could result in NMDA receptors with reduced affinities for glycine and glutamate. It is hypothesized that such alterations in NMDA receptor subunit composition may explain the neuroprotective effects produced by chronic ACPC.