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

乙醇的许多药理和生理作用已被 推测是通过中枢神经系统中含有GABA的神经元系统介导的。 GABA受体作为包含以下受体的复合体的一部分而存在 苯二氮卓类(BDZ)、巴比妥酸盐和氯离子通道。至 考察了乙醇对该络合物的影响，研究了该络合物的结合 配体35-S-叔丁基二环硫代硫酸酯的性质 它与氯离子通道的调节位点相互作用，在 C57B1小鼠大脑皮层和小脑的细胞膜 没有乙醇。在溴离子存在的体外条件下，乙醇 产生剂量依赖的Tbps结合抑制，但没有 增强GABA或戊巴比妥对Tbps结合的抑制作用。在 在氯离子存在下，乙醇对TBP的抑制作用较弱 有约束力的。然而，在这些条件下，GABA和戊巴比妥 对皮层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TBP的刺激作用 有约束力的。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已经发展起来。 亚胺基苯并二氮类药物Ro15-4513的行为研究报告 拮抗乙醇对氯离子转运的影响 乙醇对大鼠的醉酒作用，已有报道。在老鼠身上， Ro15-4513拮抗乙醇的共济失调作用 与BZD受体的相互作用。然而，Ro15-4513并没有激怒 乙醇的降温作用。结果表明，Ro15-4513不是 乙醇的作用的一般拮抗者，但某些特定的 乙醇的作用可能是通过与GABA-BZD的相互作用来实现的 受体-氯离子通道复合体。

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.