Dizocilpine maleate (MK-801) is a highly potent, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Although it has been suggested that dizocilpine may be beneficial in alleviating some symptoms of ethanol withdrawal, a rigorous evaluation of beneficial versus detrimental (phencyclidine-like) actions has not been done. The objective of the present investigation was to explore whether dizocilpine protects against ethanol withdrawal-induced increases in seizure susceptibility without being compromised by its phencyclidine-like behavioral actions. The effects of dizocilpine were assessed by using seizure threshold determinations and scoring of open field behaviors. Low dose dizocilpine administration preferentially protected against bicuculline seizure induction in ethanol-withdrawn female rats when compared with findings in ethanol-withdrawn male rats. In contrast, we found dramatic reductions in dizocilpine-induced open field behaviors during ethanol withdrawal in both male and female rats compared with findings for pair-fed control animals. [3H]MK-801 binding analysis ruled out changes in cerebral cortex or hippocampus receptor density or affinity as having a primary role in these differential responses. Taken together, our findings from these studies indicate that there are complex neuroadaptations in NMDA receptor systems after persistent ethanol exposure, manifested as either enhanced or reduced responses, depending on the measure used.