Weiner J L, Gu C, Dunwiddie T V
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
J Neurophysiol. 1997 Mar;77(3):1306-12. doi: 10.1152/jn.1997.77.3.1306.
The actions of ethanol on gamma-aminobutyric acid-A (GABAA) receptor-mediated synaptic transmission in rat hippocampal CA1 neurons remain controversial. Recent studies have reported that intoxicating concentrations of ethanol (10-100 mM) can potentiate, inhibit, or have no effect on GABAA receptor-mediated synaptic responses in this brain region. The essential determinants of ethanol sensitivity have not been defined; however, GABAA receptor subunit composition, as well as posttranslational modifications of these receptors, have been suggested as important factors in conferring ethanol sensitivity to the GABAA receptor complex. Multiple types of GABAA receptor-mediated synaptic responses have been described within individual hippocampal CA1 neurons. These responses have been shown to differ in some of their physiological and pharmacological properties. In the present study we tested hypothesis that some of the disparate findings concerning the effects of ethanol may have resulted from differences in the ethanol sensitivity of GABAA receptor-mediated synapses on single CA1 pyramidal cells. Electrical stimulation adjacent to the stratum pyramidale (proximal) and within the stratum lacunosum-moleculare (distal) activated nonoverlapping populations of GABAA receptors on rat hippocampal CA1 neurons. Proximal inhibitory postsynaptic currents (IPSCs) decayed with a single time constant and were significantly potentiated by ethanol at all concentrations tested (40, 80, and 160 mM). Distal IPSCs had slower decay rates that were often described better by the sum of two exponentials and were significantly less sensitive to ethanol at all concentrations tested. Three other allosteric modulators of GABAA receptor function with well-defined GABAA receptor subunit requirements, pentobarbital, flunitrazepam, and zolpidem, potentiated proximal and distal GABAA IPSCs to the same extent. These results demonstrate that the ethanol sensitivity of GABAA receptors can differ, not only between brain regions but within single neurons. These findings offer a possible explanation for the conflicting results of previous studies on ethanol modulation of GABAA receptor-mediated synaptic transmission in rat hippocampal CA1 neurons.
乙醇对大鼠海马CA1神经元中γ-氨基丁酸A（GABAA）受体介导的突触传递的作用仍存在争议。最近的研究报告称，中毒浓度的乙醇（10 - 100 mM）可增强、抑制或对该脑区GABAA受体介导的突触反应无影响。乙醇敏感性的基本决定因素尚未明确；然而，GABAA受体亚基组成以及这些受体的翻译后修饰，被认为是赋予GABAA受体复合物乙醇敏感性的重要因素。在单个海马CA1神经元内已描述了多种类型的GABAA受体介导的突触反应。这些反应在其一些生理和药理特性上已显示出不同。在本研究中，我们检验了这样一个假设，即关于乙醇作用的一些不同发现可能是由于单个CA1锥体细胞上GABAA受体介导的突触的乙醇敏感性差异所致。在锥体层附近（近端）和腔隙-分子层内（远端）进行电刺激，可激活大鼠海马CA1神经元上不重叠的GABAA受体群体。近端抑制性突触后电流（IPSCs）以单一时间常数衰减，并且在所有测试浓度（40、80和160 mM）下均被乙醇显著增强。远端IPSCs具有较慢的衰减速率，通常用两个指数之和能更好地描述，并且在所有测试浓度下对乙醇的敏感性显著较低。另外三种对GABAA受体功能具有明确GABAA受体亚基要求的变构调节剂，戊巴比妥、氟硝西泮和唑吡坦，对近端和远端GABAA IPSCs的增强程度相同。这些结果表明，GABAA受体的乙醇敏感性不仅在脑区之间存在差异，而且在单个神经元内也存在差异。这些发现为先前关于乙醇对大鼠海马CA1神经元中GABAA受体介导的突触传递调节的研究结果相互矛盾提供了一种可能的解释。
