Mehta A K, Ticku M K
Department of Pharmacology, University of Texas Health Science Center, San Antonio.
J Pharmacol Exp Ther. 1988 Aug;246(2):558-64.
The interaction of ethanol with gamma-aminobutyric acid (GABA)-mediated 36-Cl-influx and its modulation by various drugs was investigated in C57 mice spinal cord cultured neurons. Ethanol (5-100 mM) potentiated the effect of GABA on 36Cl-influx; whereas at concentrations greater than or equal to 50 mM ethanol activated Cl- channels directly. The effect of ethanol was specific for GABAA receptor-gated Cl- channels, as ethanol did not potentiate glycine-induced 36Cl-influx in the same neurons. Both the enhancing and direct effects of ethanol on 36Cl-influx were blocked by GABA antagonists like bicuculline, picrotoxinin and inverse agonists of the benzodiazepine site like the imidazodiazepine R015-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5 alpha], [1,4]benzodiazepine-3-carboxylate) and N-methyl-beta-carboline-3-carboxamide (FG-7142). Ethanol potentiating effect of GABA-induced 36Cl-influx was also reversed by methyl-6,7-dimethyl-4-ethyl-beta-carboline-3-carboxylate. The effects of the inverse agonists were blocked by the benzodiazepine receptor antagonist R015-1788. Both R015-4513 and FG-7142 reversed direct and GABA potentiating effects of ethanol effect at concentrations lower than those that exhibit inverse agonistic activity in the 36Cl-influx assay in cultured neurons. These results suggest that ethanol facilitation of GABAAergic transmission involves GABA receptor-gated Cl- channels and that this interaction may be responsible for some of the pharmacological effects of ethanol.
在C57小鼠脊髓培养神经元中研究了乙醇与γ-氨基丁酸（GABA）介导的³⁶Cl⁻内流的相互作用及其受各种药物的调节。乙醇（5 - 100 mM）增强了GABA对³⁶Cl⁻内流的作用；而在浓度大于或等于50 mM时，乙醇直接激活Cl⁻通道。乙醇的作用对GABAA受体门控的Cl⁻通道具有特异性，因为乙醇在相同神经元中并未增强甘氨酸诱导的³⁶Cl⁻内流。乙醇对³⁶Cl⁻内流的增强和直接作用均被GABA拮抗剂如荷包牡丹碱、印防己毒素以及苯二氮䓬位点的反向激动剂如咪唑并二氮䓬R015 - 4513（8 - 叠氮基 - 5,6 - 二氢 - 5 - 甲基 - 6 - 氧代 - 4H - 咪唑并[1,5α],[1,4]苯二氮䓬 - 3 - 羧酸乙酯）和N - 甲基 - β - 咔啉 - 3 - 甲酰胺（FG - 7142）所阻断。甲基 - 6,7 - 二甲基 - 4 - 乙基 - β - 咔啉 - 3 - 羧酸酯也可逆转乙醇对GABA诱导的³⁶Cl⁻内流的增强作用。反向激动剂的作用被苯二氮䓬受体拮抗剂R015 - 1788所阻断。在培养神经元的³⁶Cl⁻内流测定中，R015 - 4513和FG - 7142在低于表现出反向激动活性的浓度时即可逆转乙醇的直接作用和对GABA的增强作用。这些结果表明，乙醇对GABAA能传递的促进作用涉及GABA受体门控的Cl⁻通道，并且这种相互作用可能是乙醇某些药理作用的原因。
