Department of Psychiatry and Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Mol Cell Neurosci. 1992 Jun;3(3):251-8. doi: 10.1016/1044-7431(92)90045-4.
Chronic ethanol exposure alters muscimol, pentobarbital, and benzodiazepine agonist and inverse agonist effects on the function of GABA(A) receptor-gated Cl(-) channels in the central nervous system (CNS). We have recently shown that prolonged ethanol inhalation reduces the expression of GABA(A) receptor alpha1 and alpha2 subunit mRNAs in the rat cerebral cortex, with no effect on the level of alpha3 subunit transcripts, glutamic acid decarboxylase mRNA levels, or poly(A)(+) RNA levels. In the present study, rats were administered alcohol by liquid diet for 2 weeks using a pair-fed design. GABA(A) receptor alpha subunit mRNA levels were quantified by Northern analysis using specific cRNA probes. GABA(A) receptor alpha1 subunit mRNA levels were reduced in the cerebral cortex to the same extent as previously reported following prolonged ethanol inhalation. In the cerebellum, chronic ethanol ingestion reduced the levels of GABA(A) receptor alpha1 subunit mRNAs (4.8 and 4.4 kb) by 20-30% and increased the levels of GABA(A) receptor a6 subunit mRNA (2.7 kb) by 45%. GABA(A) receptor alpha2 and alpha3 subunit mRNAs were not detected in the cerebellum. Glutamic acid decarboxylase mRNA levels as well as poly(A)(+) RNA levels were not significantly altered following chronic ethanol exposure by liquid diet. Acute ethanol administration had no effect on GABA(A) receptor a6 subunit mRNA levels. However, acute administration of both Ro15-4513 and its vehicle control altered GABA(A) receptor alpha6 subunit mRNA levels in the cerebellum. Since GABA(A) receptor alpha6 subunits contain recognition sites for Ro15-4513, an inverse agonist, and an ethanol antagonist, the elevation in the expression of these subunits following chronic ethanol ingestion may account for increased sensitivity to inverse agonists after chronic ethanol administration and possibly contribute to the withdrawal syndrome. These data also suggest that chronic ethanol exposure regulates GABA(A) receptor gene expression by differential effects on the synthesis of specific subunits of GABA(A) receptors in the CNS.
慢性乙醇暴露改变了 muscimol、戊巴比妥和苯二氮䓬类激动剂和反向激动剂对中枢神经系统 (CNS) 中 GABA(A) 受体门控 Cl(-) 通道功能的影响。我们最近发现，长期乙醇吸入会降低大鼠大脑皮层中 GABA(A) 受体α1 和α2 亚基 mRNA 的表达，而对α3 亚基转录本、谷氨酸脱羧酶 mRNA 水平或 poly(A)(+) RNA 水平没有影响。在本研究中，使用配对喂养设计，通过液体饮食给大鼠给药 2 周。使用特异性 cRNA 探针通过 Northern 分析定量 GABA(A) 受体α亚基 mRNA 水平。正如之前报道的，长期乙醇吸入后，大脑皮层中 GABA(A) 受体α1 亚基 mRNA 水平降低的程度相同。在小脑，慢性乙醇摄入使 GABA(A) 受体α1 亚基 mRNA（2.7kb）的水平降低了 20-30%，并使 GABA(A) 受体 a6 亚基 mRNA 的水平增加了 45%。小脑中未检测到 GABA(A) 受体α2 和α3 亚基 mRNA。谷氨酸脱羧酶 mRNA 水平以及 poly(A)(+) RNA 水平在通过液体饮食进行慢性乙醇暴露后没有明显改变。急性乙醇给药对 GABA(A) 受体 a6 亚基 mRNA 水平没有影响。然而，急性给予 Ro15-4513 及其载体对照均改变了小脑中 GABA(A) 受体 a6 亚基 mRNA 水平。由于 GABA(A) 受体 a6 亚基含有 Ro15-4513 的识别位点，即反向激动剂和乙醇拮抗剂，因此在慢性乙醇摄入后这些亚基表达的增加可能解释了慢性乙醇给药后对反向激动剂的敏感性增加，并可能有助于戒断综合征。这些数据还表明，慢性乙醇暴露通过对中枢神经系统中 GABA(A) 受体特定亚基的合成产生不同的影响来调节 GABA(A) 受体基因表达。
