Previous studies have shown that hypoxia induces membrane lipid peroxidation and alters the N-methyl-D-aspartate (NMDA) receptor in the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypoxia-induced modification of the 3-(2-carboxypiperazin-4-yl)-1-phosphonic acid (CPP) binding site of the NMDA receptor is correlated with hypoxia-induced lipid peroxidation in brain cell membranes. Studies were performed in 18 anesthetized, ventilated piglets divided into 2 groups - 8 normoxic and 10 exposed to decreased FiO2 at different concentrations and durations to achieve various degrees of hypoxia. P2 membrane fractions were prepared and 3H-CPP binding was performed at concentrations ranging from 2.5 to 1500 nM at 23°C for 40 mins. Conjugated dienes (CDs) were measured as an index of lipid peroxidation.[ATP] and [phosphocreatine] (PCr) were measured biochemically to document tissue hypoxia. In the normoxic group the [CD] was 0.0 nmol/g brain. Bmax(receptor number) 343±80 fmole/mg protein and Kd (dissociation constant) 130±46 nM. The animals exposed to decreased FiO2 concentrations demonstrated [CDs] (nmol/g brain), Bmax (fmole/mg protein) and Kd (nM) concentrations as follows: (3.5, 142, 80), (25, 193, 118), (49, 195, 80), (56, 261, 119), (70, 326, 112), (98, 97, 47), (112, 61, 65), (117, 166, 156), (123, 59, 28) and (202, 50, 58). The results show that as the [CDs] increase both the receptor Bmax (r=0.7) and Kd (r=0.6) decrease in a linear fashion. The data demonstrate that during hypoxia progressive NMDA receptor modification occurs as lipid peroxidation increases. We speculate that the hypoxia-induced progressive modification of the NMDA recognition site may be due either to an alteration of brain cell membrane structure secondary to conjugated diene formation or to a direct modification of the receptor by hypoxia-induced free radicals. (Funded by NIH-HD-20337, MOD #6-FY94-0135, UCPR 506-93)