Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects.
Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects.
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DOI：
10.1111/j.1530-0277.2002.tb02671.x
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发表时间：
2002-08
期刊：
影响因子：
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通讯作者：
Jennifer D Thomas;S. Fleming;E. Riley
中科院分区：
文献类型：
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作者：
Jennifer D Thomas;S. Fleming;E. Riley
在发育过程中暴露于酒精会产生严重和持久的中枢神经系统损伤和随之而来的行为改变。最近的证据表明，NMDA受体介导的兴奋性毒性在撤药期间可能有助于这种损害。我们已经证明，在酒精戒断过程中用MK-801阻断NMDA受体可以减轻乙醇对大鼠行为发育的不利影响。本研究检查了MK-801减轻乙醇致畸作用的能力的剂量依赖性。方法新生大鼠幼鼠暴露于6.0 g/kg的酒精在狂欢样的方式在出生后的第6天（PD），一个时期的大脑发育相当于人类妊娠晚期的一部分。酒精管理是通过人工饲养程序完成的。乙醇处理后21小时，对幼仔腹膜内注射MK-801（0.05、0.1、0.5或1.0 mg/kg）或生理盐水溶剂的4种剂量之一。包括人工饲养的对照组和正常饲养的对照组。在PD 18-19时，监测活动水平，在PD 40-42时，评估连续空间辨别逆转学习。结果PD 6时，酒精暴露可引起活动水平的显著增加和逆转学习的缺陷。在戒断期间，接受3种较低剂量（0.05-0.5 mg/kg）MK-801之一治疗的受试者中，这些酒精诱导的行为改变显著减弱。接受高剂量MK-801（1.0 mg/kg）治疗的乙醇暴露受试者的表现与仅乙醇组无差异。结论：这些数据表明，在酒精戒断过程中NMDA受体激活的改变有助于神经病理学和随后的行为改变与发展酒精暴露。这些数据对正在经历乙醇戒断的孕妇和新生儿具有重要意义。
BACKGROUND Alcohol exposure during development can produce severe and long-lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor-mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK-801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK-801's ability to mitigate ethanol's teratogenic effects. METHODS Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge-like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty-one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK-801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18-19, activity level was monitored, and on PD 40-42, serial spatial discrimination reversal learning was assessed. RESULTS Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol-induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05-0.5 mg/kg) of MK-801 during withdrawal. The performance of ethanol-exposed subjects treated with the high dose of MK-801 (1.0 mg/kg) did not differ from that of the Ethanol Only group. CONCLUSIONS These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.