Thomas Jennifer D, Fleming S L, Riley E P
Center for Behavioral Teratology, Department of Psychology, San Diego State University, 6363 Alvarado Court, Suite 209, San Diego, CA 92120, USA.
Alcohol Clin Exp Res. 2002 Aug;26(8):1307-13. doi: 10.1097/01.ALC.0000025888.60664.D9.
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.
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.
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.
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.
发育过程中接触酒精会导致严重且持久的中枢神经系统损伤以及随之而来的行为改变。最近的证据表明，戒断期间N-甲基-D-天冬氨酸（NMDA）受体介导的兴奋性毒性可能导致这种损伤。我们已经证明，在酒精戒断期间用MK-801阻断NMDA受体会减弱乙醇对大鼠行为发育的不利影响。本研究检测了MK-801减轻乙醇致畸作用能力的剂量依赖性。
新生大鼠幼崽在出生后第6天（PD6）以类似暴饮的方式暴露于6.0 g/kg乙醇中，这一脑发育时期相当于人类妊娠晚期的一部分。通过人工饲养程序给予酒精。乙醇处理21小时后，给幼崽腹腔注射四种剂量的MK-801（0.05、0.1、0.5或1.0 mg/kg）之一或生理盐水。纳入人工饲养对照组和正常饲养对照组。在PD18 - 19监测活动水平，在PD40 - 42评估系列空间辨别反转学习。
PD6暴露于酒精导致活动水平显著增加和反转学习缺陷。在戒断期间用三种较低剂量（0.05 - 0.5 mg/kg）之一的MK-801治疗的受试者中，这些酒精诱导的行为改变显著减轻。用高剂量MK-801（1.0 mg/kg）治疗的乙醇暴露受试者的表现与仅乙醇组没有差异。
这些数据表明，酒精戒断期间NMDA受体激活的改变导致了与发育性酒精暴露相关的神经病理学及随之而来的行为改变。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。
