Mhatre M C, Pena G, Sieghart W, Ticku M K
Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
J Neurochem. 1993 Nov;61(5):1620-5. doi: 10.1111/j.1471-4159.1993.tb09795.x.
Chronic administration of ethanol results in the development of tolerance and dependence. The molecular mechanism underlying these behavioral actions of ethanol is poorly understood. Several lines of evidence have suggested that some of the pharmacological actions of ethanol are mediated via a potentiation of GABAergic transmission. Chronic ethanol administration results in a reduction in the GABAA receptor-mediated 36Cl- uptake in cortical synaptoneurosomes and primary cultured neurons. We and others have shown that it also results in a 40-50% reduction in GABAA receptor alpha-subunit mRNA levels in the rat cerebral cortex. In the present study, we investigated the expression of alpha 1, alpha 2, and alpha 3 subunits of the GABAA receptor in the cerebral cortex and the alpha 1 subunit in the cerebellum by immunoblotting using polyclonal antibodies raised against alpha 1-, alpha 2-, and alpha 3-subunit polypeptides following chronic ethanol treatment. These results reveal that chronic ethanol administration to rats results in a 61 +/- 4% reduction in level of the GABAA receptor alpha 1 subunit (51 kDa), 47 +/- 8% reduction in level of the alpha 2 subunit (53 kDa), and 30 +/- 7% reduction in level of the alpha 3 subunit (59 kDa) in the cerebral cortex and a 56 +/- 5% reduction in content of the alpha 1 subunit in the cerebellum. In summary, this ethanol-induced reduction in content of the GABAA receptor alpha subunits may underlie alterations in the GABAA receptor function and could be related to cellular adaptation to the functional disturbance caused by ethanol.
长期给予乙醇会导致耐受性和依赖性的产生。乙醇这些行为作用背后的分子机制尚不清楚。有几条证据表明，乙醇的一些药理作用是通过增强GABA能传递介导的。长期给予乙醇会导致皮质突触神经小体和原代培养神经元中GABAA受体介导的36Cl-摄取减少。我们和其他人已经表明，它还会导致大鼠大脑皮质中GABAA受体α亚基mRNA水平降低40 - 50%。在本研究中，我们使用针对α1、α2和α3亚基多肽产生的多克隆抗体，通过免疫印迹法研究了长期乙醇处理后大脑皮质中GABAA受体α1、α2和α3亚基以及小脑α1亚基的表达。这些结果表明，长期给大鼠给予乙醇会导致大脑皮质中GABAA受体α1亚基（51 kDa）水平降低61±4%，α2亚基（53 kDa）水平降低47±8%，α3亚基（59 kDa）水平降低30±7%，小脑α1亚基含量降低56±5%。总之，乙醇诱导的GABAA受体α亚基含量降低可能是GABAA受体功能改变的基础，并且可能与细胞对乙醇引起的功能紊乱的适应性有关。
