Prendergast M A, Harris B R, Mayer S, Littleton J M
Department of Psychology, University of Kentucky, Lexington 40506-0044, USA.
Alcohol Clin Exp Res. 2000 Oct;24(10):1583-92.
Long-term ethanol use and long-term tobacco use frequently occur together, which suggests concurrent dependence on ethanol and nicotine. Consequences of this form of polydrug dependence are not well understood, however. Previous evidence suggests detrimental effects of long-term ethanol and beneficial effects of nicotine exposure on neuronal viability. Thus, the present study was designed to use an organotypic hippocampal slice culture model to examine the ability of chronic and acute nicotine exposure to reduce neurotoxicity associated with withdrawal from long-term ethanol exposure.
Twenty-four hours of withdrawal after continuous 10 day ethanol exposure (50 or 100 mM in culture medium) resulted in cytotoxicity in hippocampal slice explants obtained from neonatal rat, most notably in pyramidal cell layers of the CA1 region. Exposure of slices to the N-methyl-D-aspartate receptor blocker MK-801 during ethanol withdrawal significantly reduced this toxicity. Exposure of slices to nicotine (0.1-10.0 microM) during the 24 hr withdrawal period did not reduce hippocampal damage. However, treatment of slices with nicotine (0.1-10.0 microM) during 10 days of ethanol exposure was associated with significant reductions in subsequent withdrawal-induced cytotoxicity, an effect reduced by mecamylamine coexposure with nicotine and ethanol.
These findings indicate the development of marked hippocampal neurotoxicity during withdrawal from long-term ethanol exposure that is mediated, in part, by overactivation of N-methyl-D-aspartate receptors. Furthermore, these data suggest that one consequence of concurrent dependence on ethanol and nicotine may be reduced neurological damage associated with ethanol withdrawal.
长期饮酒和长期吸烟常常同时发生，这表明存在对乙醇和尼古丁的并发依赖。然而，这种多药依赖形式的后果尚未得到充分理解。先前的证据表明，长期饮酒有有害影响，而尼古丁暴露对神经元活力有有益影响。因此，本研究旨在使用器官型海马切片培养模型，来检验慢性和急性尼古丁暴露减轻与长期乙醇暴露戒断相关的神经毒性的能力。
在连续10天乙醇暴露（培养基中浓度为50或100 mM）后24小时戒断，导致从新生大鼠获得的海马切片外植体出现细胞毒性，最明显的是在CA1区的锥体细胞层。在乙醇戒断期间，将切片暴露于N-甲基-D-天冬氨酸受体阻滞剂MK-801可显著降低这种毒性。在24小时戒断期将切片暴露于尼古丁（0.1 - 10.0 microM）并未减轻海马损伤。然而，在10天乙醇暴露期间用尼古丁（0.1 - 10.0 microM）处理切片，与随后戒断诱导的细胞毒性显著降低相关，与尼古丁和乙醇共同暴露时，美加明可减弱这种效应。
这些发现表明，长期乙醇暴露戒断期间会出现明显的海马神经毒性，部分是由N-甲基-D-天冬氨酸受体过度激活介导的。此外，这些数据表明，乙醇和尼古丁并发依赖的一个后果可能是减轻与乙醇戒断相关的神经损伤。
