Thomas M P, Monaghan D T, Morrisett R A
The Institute for Neuroscience and the Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin, Texas, USA.
J Pharmacol Exp Ther. 1998 Oct;287(1):87-97.
Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist D-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.
在一个海马外植体模型系统中，运用电生理技术研究了因慢性乙醇暴露戒断所致的兴奋性过高的突触机制。对CA1锥体细胞进行的全细胞膜片钳记录显示，急性乙醇暴露使N-甲基-D-天冬氨酸受体（NMDAR）介导的兴奋性突触后电流抑制超过40%。在35或75 mM浓度下慢性乙醇暴露6至11天，群体突触反应的快速成分（非NMDAR介导）与对照外植体相比无差异。采用长时间场电位记录（长达10小时）来监测体外的戒断过程。来自35 mM和75 mM组的乙醇暴露外植体在从慢性暴露中戒断后，突触传递的NMDAR介导成分均增加（分别为60%和89%）。仅在NMDAR功能增强后，乙醇戒断后持续观察到长时间的强直-阵挛性电图癫痫活动。这种兴奋性过高被NMDAR拮抗剂D-2-氨基-5-磷酸戊酸抑制，拮抗剂洗脱后NMDAR成分重新建立时又恢复。原位杂交研究表明，慢性乙醇暴露后外植体中NR2B亚基mRNA的表达可能增强。急性体外乙醇暴露和戒断后，NMDAR成分未观察到持久差异。这些数据表明，该系统中乙醇戒断兴奋性过高的发生可能直接取决于慢性暴露后NMDAR功能的改变。由于该区域及其他含有乙醇敏感NMDAR的区域可能作为癫痫病灶，预计NMDAR功能的长期改变会在乙醇暴露戒断后产生发作期事件潜在的阵发性去极化偏移。
