Treatment with N-methyl-D-aspartate (NMDA) receptor antagonists limits tissue damage following CNS ischemia or trauma, supporting the hypothesis that NMDA receptors participate in the pathophysiology of such injuries. An alternative approach for evaluating this hypothesis is to examine the effects of selective inhibition of NMDA receptor synthesis, using antisense oligodeoxynucleotides. In the present studies, the effects of antisense oligodeoxynucleotides directed at NMDA-R1 receptor subunit, administered intracerebroventricularly (i.c.v.) prior to injury, were evaluated in a well-defined traumatic brain injury model in rats. Outcome measures included survival, motor recovery, and histological changes. Administration of antisense oligodeoxynucleotides (15 nmol/ml twice daily x 2 days) did not alter physiological variables or motor function prior to trauma. However, such treatment significantly decreased mortality and improved behavioral recovery at 2 weeks after trauma as compared to animals treated with the corresponding sense oligodeoxynucleotides. Although cell counts in hippocampus did not differ between treatment groups, astrocyte activation as reflected by glial fibrillary astrocytic protein (GFAP) immunocytochemistry was significantly reduced in antisense treated animals. These findings provide additional evidence that NMDA receptors contribute to secondary injury after brain trauma and may suggest an alternative treatment approach.