Global metabolic insults such as ischemia/hypoxia, damage neural cells through release of excitatory amino acids and their subsequent actions at the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are highly expressed in neonatal rat brain, and the current study examines the effects of receptor blockade with MK-801 on DNA synthesis under normoxic and hypoxic conditions. At one day of age, hypoxia alone caused a decrease in [3H]thymidine incorporation into DNA throughout the brain, whereas MK-801 alone decreased incorporation selectively in regions known to be enriched in NMDA receptors. MK-801 afforded no protection from hypoxia and instead exacerbated the effects of hypoxia in the cerebellum. At 8 days of age, hypoxia alone or MK-801 alone still produced the same patterns of inhibition of DNA synthesis, but MK-801 neither prevented nor exacerbated the effects of hypoxia; animals receiving MK-801 showed a significant incidence of hypoxia-induced mortality. These data suggest that excitatory actions exerted at the NMDA receptor serve to maintain cell replication in neonatal brain and, as distinct from the situation for excitatory amino acid-induced cell death, these receptors do not participate in adverse effects of hypoxia on DNA synthesis.