Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors
Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors
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DOI：
10.1124/mol.63.1.53
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发表时间：
2003-01-01
影响因子：
3.6
通讯作者：
Olsen, RW
中科院分区：
文献类型：
--
作者：
Cagetti, E;Liang, J;Olsen, RW
乙醇的药理靶点之一是GABA(A)受体（GABAR），其功能和表达在长期给药后发生改变。这些变化的细节在不同的实验模型中有所不同。在酒精依赖的慢性间歇乙醇（CIE）模型中，大鼠暴露于间歇性的酒精中毒和戒断，导致行为兴奋性的引火状态。这可能伴随着GABAR表达和生理上的因果变化。本研究进一步探讨了CIE对GABAR功能和表达的影响。CIE被证实为人类酒精戒断综合征（AWS）的模型，表现出焦虑水平的增加；安定提高了测试中的表现。此外，CIE大鼠对苯二氮卓类药物和类固醇麻醉剂的催眠反应显著降低，对巴比妥酸盐的敏感性降低，但对异丙酚没有影响。免疫印迹显示，CIE大鼠海马区α 1和δ表达减少，γ 2和α 4亚基表达增加，证实了地西帕姆对乙基-8-叠氮-5,6-二氢-5-甲基-6-氧- 4h -咪唑（1,5- α）（1,4）苯二氮平-3-羧酸酯（Ro15-4513）的不敏感结合增加。gamma2S和gamma1亚基mRNA水平升高。CIE大鼠海马切片记录显示，与对照大鼠相比，GABAR介导的CA1锥体细胞中微型抑制性突触后电流（mIPSCs）的衰减时间缩短，GABAR正调物对mIPSCs的增强也减弱。然而，偏爱α 4的苯二氮卓类配体bretazenil和Ro15-4513对mIPSC的增强作用保持不变，并分别增强。这些数据表明，在CIE后GABAR发生特异性改变，可能是过度兴奋性和乙醇依赖性发展的基础。
One of the pharmacological targets of ethanol is the GABA(A) 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.