Knapp D J, Braun C J, Duncan G E, Qian Y, Fernandes A, Crews F T, Breese G R
Bowles Center for Alcohol Studies, and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alcohol Clin Exp Res. 2001 Nov;25(11):1662-72.
Inhibition of NMDA receptor function in brain is believed to be an important action of ethanol (EtOH). To investigate EtOH inhibition of NMDA receptor responses in vivo, the interaction of these agents in brain after different routes of administration were investigated by using transcription factor Fos protein expression to follow NMDA receptor activation and EtOH inhibition of this response.
The induction of Fos-like immunoreactivity (Fos-LI) in 38 regions of the rat brain was measured 2 hr after treatment with NMDA, EtOH, or both. To determine the relative contribution of abdominal drug effects on Fos induction, rats received either intraperitoneal (ip) or intragastric (ig) EtOH and ip or intravenous (iv) NMDA. Rats received EtOH (2.5 g/kg ip or 4 g/kg ig) or vehicle 15 min before NMDA (125 mg/kg ip or 60 mg/kg iv) or vehicle.
For the 38 forebrain regions examined, ip and iv NMDA significantly induced Fos-LI in 13 and 32 regions, respectively. These effects occurred without elicitation of tonic-clonic seizure activity and were strong after iv NMDA in the frontal, prefrontal, and cingulate cortices, supraoptic nucleus, anterior lateral septum, and dentate gyrus. For EtOH, prominent Fos-LI induction was found in the central amygdala, dorsolateral bed nucleus of the stria terminalis, Edinger-Westphal nucleus, and paraventricular hypothalamus. Despite ip and ig EtOH induction of Fos-LI in these regions, the major effect of EtOH was to block NMDA-induced Fos-LI in 8 of 13 (ip) and 27 of 32 (ig) of the NMDA-positive regions, respectively, including retrosplenial, cingulate, and medial prefrontal cortices, central amygdala, and taenia tecta.
These results provide new evidence for the regionally specific functional interactions of EtOH on NMDA receptors in vivo. Moreover, these results support efforts to identify brain region-specific targets for EtOH and EtOH-induced changes in gene expression.
大脑中N-甲基-D-天冬氨酸（NMDA）受体功能的抑制被认为是乙醇（EtOH）的重要作用。为了研究EtOH在体内对NMDA受体反应的抑制作用，通过使用转录因子Fos蛋白表达来追踪NMDA受体激活以及EtOH对该反应的抑制，研究了不同给药途径后这些药物在大脑中的相互作用。
在用NMDA、EtOH或两者处理后2小时，测量大鼠大脑38个区域中Fos样免疫反应性（Fos-LI）的诱导情况。为了确定腹腔内药物作用对Fos诱导的相对贡献，大鼠接受腹腔内（ip）或胃内（ig）EtOH以及腹腔内或静脉内（iv）NMDA。大鼠在接受NMDA（125mg/kg腹腔内或60mg/kg静脉内）或溶剂前15分钟接受EtOH（2.5g/kg腹腔内或4g/kg胃内）或溶剂。
在所检查的38个前脑区域中，腹腔内和静脉内NMDA分别在13个和32个区域显著诱导Fos-LI。这些作用在未引发强直-阵挛性癫痫活动的情况下发生，静脉内给予NMDA后，在额叶、前额叶和扣带回皮质、视上核、前外侧隔和齿状回中作用强烈。对于EtOH，在中央杏仁核、终纹床核背外侧、动眼神经副核和室旁下丘脑中发现了显著的Fos-LI诱导。尽管腹腔内和胃内EtOH在这些区域诱导了Fos-LI，但EtOH的主要作用是分别在13个NMDA阳性区域中的8个（腹腔内）和32个（胃内）中的27个区域阻断NMDA诱导的Fos-LI，包括压后皮质、扣带回和内侧前额叶皮质、中央杏仁核和带状盖。
这些结果为EtOH在体内对NMDA受体的区域特异性功能相互作用提供了新证据。此外，这些结果支持了识别EtOH和EtOH诱导的基因表达变化的脑区特异性靶点的努力。
