Mitsuyama H, Little K Y, Sieghart W, Devaud L L, Morrow A L
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
Alcohol Clin Exp Res. 1998 Jun;22(4):815-22.
Animal studies have shown that chronic ethanol consumption produces physical dependence upon ethanol and alters gamma-aminobutyric acid-A (GABA(A)) receptor subunit gene expression in brain. Although extensive investigation has been conducted in animal models, relatively little work has been performed directly on human alcoholic brain tissue to determine if there are alterations in GABA(A) receptor gene expression. In this study, GABA(A) receptor alpha1, alpha4, and beta3 subunit mRNA and peptide expression in postmortem frontal cortex from human alcoholics (n = 15) and age- and sex-matched controls (n = 13) were measured by quantitative, competitive reverse transcription polymerase chain reaction and Western blot analysis. GABA(A) receptor beta3 subunit mRNA expression was 35% greater (p < 0.05) in alcoholics, compared with nonalcoholic controls. We found no significant difference in alpha1 and alpha4 subunit mRNA levels between groups. However, there was a trend toward greater (21%) alpha1 subunit mRNA expression. There was no difference in alpha1, alpha4, or beta2/3 subunit peptide levels in frontal cortex between controls and alcoholics. Neither the age of the subjects nor the postmortem interval correlated with mRNA or peptide levels. Blood ethanol content also did not correlate with mRNA or peptide expression in alcoholic samples. These data suggest that GABA(A) receptor adaptations, resulting from prolonged alcohol consumption in human alcoholics, may differ from animal models of alcohol dependence. These differences may be related to the longevity of alcohol exposure in human alcoholics, as well as variability in the dependence/withdrawal state of the human subjects. Therefore, further studies in human postmortem brain tissue are warranted.
动物研究表明，长期摄入乙醇会导致对乙醇产生身体依赖，并改变大脑中γ-氨基丁酸-A（GABA(A)）受体亚基的基因表达。尽管已经在动物模型中进行了广泛的研究，但直接对人类酒精性脑组织进行的研究相对较少，以确定GABA(A)受体基因表达是否存在改变。在本研究中，通过定量竞争性逆转录聚合酶链反应和蛋白质印迹分析，测量了人类酗酒者（n = 15）和年龄及性别匹配的对照组（n = 13）死后额叶皮质中GABA(A)受体α1、α4和β3亚基的mRNA和肽表达。与非酒精性对照组相比，酗酒者中GABA(A)受体β3亚基的mRNA表达高35%（p < 0.05）。我们发现两组之间α1和α4亚基的mRNA水平没有显著差异。然而，α1亚基的mRNA表达有升高21%的趋势。对照组和酗酒者额叶皮质中α1、α4或β2/3亚基的肽水平没有差异。受试者的年龄和死后间隔时间均与mRNA或肽水平无关。血液乙醇含量也与酗酒者样本中的mRNA或肽表达无关。这些数据表明，人类酗酒者长期饮酒导致的GABA(A)受体适应性变化可能与酒精依赖的动物模型不同。这些差异可能与人类酗酒者酒精暴露的持续时间以及人类受试者依赖/戒断状态的变异性有关。因此，有必要对人类死后脑组织进行进一步研究。
