Chronic, but not acute, nicotine exposure attenuates ethanol withdrawal-induced hippocampal damage in vitro

Background: Long-term ethanol use and long-term tobacco use frequently occu r together, which suggests concurrent dependence on ethanol and nicotine. C onsequences of this form of polydrug dependence are not well, understood, h owever. Previous evidence suggests detrimental effects of long-term ethanol and beneficial effects of nicotine exposure on neuronal viability. Thus, t he present study was designed to use an organotypic hippocampal slice cultu re model to examine the ability of chronic and acute nicotine exposure to r educe neurotoxicity associated with withdrawal from long-term ethanol expos ure. Methods and Results: Twenty-four hours of withdrawal after continuous 10 da y ethanol exposure (50 or 100 mM in culture medium) resulted in cytotoxicit y in hippocampal slice explants obtained from neonatal rat, most notably in pyramidal cell layers of the CA1 region. Exposure of slices to the N-methy l-D-aspartate receptor blocker MK-801 during ethanol withdrawal significant ly reduced this toxicity. Exposure of slices to nicotine (0.1-10.0 mu M) du ring the 24 hr withdrawal period did not reduce hippocampal damage. However , treatment of slices with nicotine (0.1-10.0 ELM) during 10 days of ethano l exposure was associated with significant reductions in subsequent withdra wal-induced cytotoxicity, an effect reduced by mecamylamine coexposure with nicotine and ethanol. Conclusions: These findings indicate the development of marked hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is med iated, in part, by overactivation of N-methyl-D-aspartate receptors. Furthe rmore, these data suggest that one consequence of concurrent dependence on ethanol and nicotine may be reduced neurological damage associated with eth anol withdrawal.