In vitro effects of ethanol withdrawal and spermidine on viability of hippocampus from male and female rat

Background: Long-term ethanol dependence results in neuronal adaptation tha t likely contributes to ethanol withdrawal-induced central nervous system e xcitability and, potentially, neurotoxicity. This has been suggested to res ult, in part, from increased release of or response to endogenous polyamine s. 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 pol yamine spermidine on neurotoxicity associated with withdrawal from long-ter m ethanol exposure by using organotypic hippocampal slice cultures derived from male and female rats. Methods and Results: Twenty-four hours of withdrawal after continuous 10 da y ethanol exposure (100 mM in culture medium) resulted in cytotoxicity in h ippocampal slice explants obtained from both sexes. This was most evident i n pyramidal cell layers of the CA1 region, and no sex differences were obse rved in the severity of damage. Exposure of explants from both sexes to the NMDA blocker MK-801 during ethanol withdrawal significantly reduced this t oxicity. In control cultures, exposure to spermidine (100 muM) alone produc ed significant and similar cytotoxicity in hippocampal explants of male and female rats. Exposure to spermidine (100 muM) during ethanol withdrawal si gnificantly increased cytotoxicity in all regions of explants. In the CA3 r egion, spermidine-potentiation of ethanol withdrawal damage was significant ly greater in explants from female rats compared with those from male rats. Conclusions: These data demonstrate the presence of significant hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is me diated, in part, by overactivation of NMDA receptors. Furthermore, these fi ndings suggest that the central nervous system of females may be more susce ptible than that of males to polyamine-mediated neuronal damage during with drawal from long-term ethanol exposure.