Floyd Donald W, Friedman David P, Daunais James B, Pierre Peter J, Grant Kathleen A, McCool Brian A
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
J Pharmacol Exp Ther. 2004 Dec;311(3):1071-9. doi: 10.1124/jpet.104.072025. Epub 2004 Jul 27.
We have recently demonstrated that chronic ethanol ingestion alters the functional and pharmacological properties of GABAA receptors measured in acutely isolated rat lateral/basolateral amygdala neurons, a limbic forebrain region involved with fear-learning and innate anxiety. To understand relevance of these results in the context of primates, we have examined the effects of long-term ethanol self-administration on basolateral amygdala GABAA receptor pharmacology and expression in cynomolgus macaques (Macaca fascicularis). The impact of this 18-month-long exposure on GABAA receptor function was assessed in acutely isolated neurons from basolateral amygdala with whole-cell patch-clamp electrophysiology. Neurons from control animals expressed maximal current densities that were not significantly different from the maximal current densities of neurons from ethanol-treated animals. However, the GABA concentration-response relationships from ethanol-exposed neurons were significantly right-shifted compared with control neurons. These adaptations were associated with significant alterations in some characteristics of macroscopic current desensitization. To understand the mechanism governing these adaptations, we quantified GABAA alpha subunit mRNAs in basolateral amygdala from the same animals. mRNA levels of the alpha2 and alpha3 subunits were significantly decreased, whereas decreases in alpha1 expression only approached statistical significance. There were no changes in alpha4 mRNA levels. These findings indicate that ethanol-induced alterations in GABAA function may be regulated in part by selective changes in the expression of particular alpha subunits. We conclude that adaptations of basolateral amygdala GABAA receptors after long-term ethanol self-administration by the cynomolgus macaque are similar, but not identical, to those described in rodents after a brief forced ethanol exposure.
我们最近证明，长期摄入乙醇会改变急性分离的大鼠外侧/基底外侧杏仁核神经元中GABAA受体的功能和药理学特性，该边缘前脑区域与恐惧学习和先天性焦虑有关。为了了解这些结果在灵长类动物中的相关性，我们研究了长期乙醇自我给药对食蟹猴基底外侧杏仁核GABAA受体药理学和表达的影响。通过全细胞膜片钳电生理学，在急性分离的基底外侧杏仁核神经元中评估了这种长达18个月的暴露对GABAA受体功能的影响。对照动物的神经元表达的最大电流密度与乙醇处理动物的神经元的最大电流密度没有显著差异。然而，与对照神经元相比，乙醇暴露神经元的GABA浓度-反应关系显著右移。这些适应性变化与宏观电流脱敏的一些特征的显著改变有关。为了了解控制这些适应性变化的机制，我们对同一动物基底外侧杏仁核中的GABAAα亚基mRNA进行了定量。α2和α3亚基的mRNA水平显著降低，而α1表达的降低仅接近统计学显著性。α4 mRNA水平没有变化。这些发现表明，乙醇诱导的GABAA功能改变可能部分受特定α亚基表达的选择性变化调节。我们得出结论，食蟹猴长期乙醇自我给药后基底外侧杏仁核GABAA受体的适应性变化与啮齿动物短暂强制乙醇暴露后所描述的变化相似，但不完全相同。
