Long-term ethanol dependence results in neuronal adaptation that likely contributes to ethanol withdrawal-induced central nervous system excitability and, potentially, neurotoxicity. This has been suggested to result, in part, from increased release of or response to endogenous polyamines. Furthermore, it has been reported that neurological difficulties related to ethanol dependence and withdrawal may be more severe in female than in male alcoholics. Thus, we designed this study to examine effects of the polyamine spermidine on neurotoxicity associated with withdrawal from long-term ethanol exposure by using organotypic hippocampal slice cultures derived from male and female rats.