Cagetti Elisabetta, Liang Jing, Spigelman Igor, Olsen Richard W
Department of Molecular and Medical Pharmacology, School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1735, USA.
Mol Pharmacol. 2003 Jan;63(1):53-64. doi: 10.1124/mol.63.1.53.
One of the pharmacological targets of ethanol is the GABAA receptor (GABAR), whose function and expression are altered after chronic administration of ethanol. The details of the changes differ between experimental models. In the chronic intermittent ethanol (CIE) model for alcohol dependence, rats are exposed to intermittent episodes of intoxicating ethanol and withdrawal, leading to a kindling-like state of behavioral excitability. This is accompanied by presumably causal changes in GABAR expression and physiology. The present study investigates further the effect of CIE on GABAR function and expression. CIE is validated as a model for human alcohol withdrawal syndrome (AWS) by demonstrating increased level of anxiety; diazepam improved performance in the test. In addition, CIE rats showed remarkably reduced hypnotic response to a benzodiazepine and a steroid anesthetic, reduced sensitivity to a barbiturate, but not propofol. Immunoblotting revealed decrease in alpha1 and delta expression and increase in gamma2 and alpha4 subunits in hippocampus of CIE rats, confirmed by an increase in diazepam-insensitive binding for ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-alpha)(1,4)benzodiazepine-3-carboxylate (Ro15-4513). Elevated mRNA levels were shown for the gamma2S and gamma1 subunits. Recordings in hippocampal slices from CIE rats revealed that the decay time of GABAR-mediated miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal cells was decreased, and potentiation of mIPCSs by positive modulators of GABAR was also reduced compared with control rats. However, mIPSC potentiation by the alpha4-preferring benzodiazepine ligands bretazenil and Ro15-4513 was maintained, and increased, respectively. These data suggest that specific alterations in GABAR occur after CIE and may underlie the development of hyperexcitability and ethanol dependence.
乙醇的药理学靶点之一是γ-氨基丁酸A受体（GABAR），长期给予乙醇后其功能和表达会发生改变。不同实验模型中变化的细节有所不同。在酒精依赖的慢性间歇性乙醇（CIE）模型中，大鼠暴露于间歇性的中毒性乙醇及戒断状态，导致行为兴奋性出现类似点燃的状态。这伴随着GABAR表达和生理学上可能的因果变化。本研究进一步探究CIE对GABAR功能和表达的影响。通过证明焦虑水平升高，CIE被确认为人类酒精戒断综合征（AWS）的模型；地西泮可改善该测试中的表现。此外，CIE大鼠对苯二氮䓬和类固醇麻醉剂的催眠反应显著降低，对巴比妥类药物的敏感性降低，但对丙泊酚不敏感。免疫印迹显示CIE大鼠海马中α1和δ表达减少，γ2和α4亚基增加，这通过对8-叠氮基-5,6-二氢-5-甲基-6-氧代-4H-咪唑并(1,5-α)(1,4)苯并二氮䓬-3-羧酸乙酯（Ro15-4513）的地西泮不敏感结合增加得到证实。γ2S和γ1亚基的mRNA水平升高。对CIE大鼠海马切片的记录显示，CA1锥体细胞中GABAR介导的微小抑制性突触后电流（mIPSCs）的衰减时间缩短，与对照大鼠相比，GABAR正性调节剂对mIPCSs的增强作用也降低。然而，对α4优先的苯二氮䓬配体布瑞西坦和Ro15-4513的mIPSC增强作用分别得以维持和增强。这些数据表明，CIE后GABAR发生了特定改变，可能是兴奋性过高和乙醇依赖发展的基础。
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