ETHANOL ACTIONS AT THE GABA-BDZ-BARBITURATE RECEPTOR/CHLORIDE IONOPHORE

乙醇的许多药理学和生理学作用已被证实。 推测通过CNS中含GABA的神经元系统介导。 GABA受体作为含有受体的复合物的一部分存在， 苯二氮卓类药物（BDZ）、巴比妥类药物和氯离子通道。 到 为了研究乙醇对这种复合物的影响，我们研究了 配体35-S-叔丁基双环硫代磷酸酯（35-5-TBPS）的性质 它与氯离子通道的调节位点相互作用， C57 B1小鼠皮质和小脑的膜， 没有乙醇。 在体外溴离子存在下，乙醇 对TBPS结合产生剂量依赖性抑制，但不 增强GABA或戊巴比妥对TBPS结合的抑制作用。 在 存在氯离子时，乙醇对TBPS的抑制作用较弱 约束力 然而，在这些条件下，GABA和戊巴比妥 对皮质中TBPS结合的双相效应，以及低浓度的 乙醇降低了这些化合物对TBPS的刺激作用 约束力 为了关联乙醇对配体结合的影响， 具有功能反应的完整细胞（例如GABA刺激的氯化物 通量），小脑颗粒细胞的原代培养物已经开发出来。 一种亚氨基苯二氮卓类药物Ro 15 -4513的行为研究报告， 拮抗乙醇对氯离子转运的影响， 酒精中毒作用的大鼠，已经进行了。 在小鼠中， Ro 15 -4513拮抗乙醇的共济失调作用，显然是通过 与BZD受体相互作用。 然而，Ro 15 -4513不拮抗 乙醇的低温效应。 结果表明，Ro 15 -4513不是 乙醇作用的一般拮抗剂，但某些特定的 乙醇的作用可能是通过与GABA-BZD的相互作用介导的 受体-氯离子通道复合物。

Many pharmacological and physiological effects of ethanol have been postulated to be mediated via GABA-containing neuronal systems in the CNS. The GABA receptor exists as part of a complex containing receptors for benzodiazepines (BDZ), barbiturates and the chloride ion channel. To examine the effects of ethanol on this complex, we have studied the binding properties of 35-S-t-butylbicyclophosphorothionate (35-5-TBPS), a ligand which interacts with the regulatory site of the chloride ion channel, in membranes of cortex and cerebellum of C57B1 mice in the presence and absence of ethanol. In the presence of bromide ion in vitro, ethanol produced a dose-dependent inhibition of TBPS binding, but did not potentiate the inhibition of TBPS binding by GABA or pentobarbital. In the presence of chloride ion, ethanol was less potent at inhibiting TBPS binding. However, under these conditions, GABA and pentobarbital had biphasic effects on TBPS binding in cortex, and low concentrations of ethanol reduced the stimulatory effects of these compounds on TBPS binding. In order to correlate effects of ethanol on ligand binding in intact cells with a functional response (e.g. GABA-stimulated chloride flux), primary cultures of cerebellar granule cells have been developed. Behavioral studies of an imidobenzodiazepine, Ro15-4513, reported to antagonize the effects of ethanol on chloride transport and the intoxicating effect of ethanol in rats, have been performed. In mice, Ro15-4513 antagonized the ataxic effect of ethanol, apparently by interaction with a BZD receptor. However, Ro15-4513 did not antagonize the hypothermic effect of ethanol. The results indicate that Ro15-4513 is not a general antagonist of ethanol's actions, but that certain specific effects of ethanol may be mediated by an interaction with the GABA-BZD receptor-chloride channel complex.