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

乙醇的许多药理作用被认为是由 通过中枢神经系统中含有GABA的神经元系统。GABA受体存在 作为含有苯二氮卓类(BDZ)受体的复合体的一部分， 巴比妥酸盐和氯离子通道。考察……的影响 乙醇对该络合物的结合性能进行了研究。 相互作用的配体35-S-叔丁基二环硫代硫酸酯(35-S-Tbps) 与大脑皮层膜上氯离子通道的调节位置 C57B1小鼠在乙醇存在和不存在的情况下的小脑。在……里面 体外加入乙醇对TBP的抑制作用呈剂量依赖性 小脑和皮质均有结合(IC-50约300 mm)。在一次 生理上可获得的乙醇浓度，即100 mm， Tbps结合受到了实质性的抑制。GABA和戊巴比妥 也抑制大脑皮层和小脑中35-S-Tbps的结合，以及 乙醇并不能增强这些试剂的作用。我们最初的 结果表明，在体内慢性给药后， 产生功能耐受性和身体依赖性，耐受性 乙醇对Tbps结合的体外影响不发生，而乙醇对Tbps结合的影响 GABA和巴比妥酸盐也没有变化。与结果形成对比的是 TBPS，慢性乙醇处理导致小鼠的能力降低。 在体外测试中加入戊巴比妥以刺激BDZ (3-H-呋喃硝基安定)(Flu)在大脑皮层和小脑结合。类似 结果是在长期喂食巴比妥酸盐的动物身上发现的。这个 结果支持这样一种假设，即黄连的某些药理作用 乙醇可能来自与GABA-BDZ-巴比妥酸受体的相互作用 很复杂。慢性乙醇治疗可能导致适应性 在最初受以下因素影响的站点以外的站点发生的更改 乙醇，但这会改变复合体的整体功能。这些 生化改变可能与不同方面的 对乙醇的耐受性、交叉耐受性和身体依赖性。

Many pharmacological 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-S-TBPS), a ligand that 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 vitro addition of ethanol produced a dose-dependent inhibition of TBPS binding in both cerebellum and cortex (IC-50 approximately 300 mM). At a concentration of ethanol that is physiologically attainable, i.e., 100 mM, there was substantial inhibition of TBPS binding. GABA and pentobarbital also inhibited the binding of 35-S-TBPS in cortex and cerebellum, and ethanol did not potentiate the actions of these agents. Our initial results indicate that after chronic in vivo ethanol administration, which produces functional tolerance and physical dependence, tolerance to the in vitro effects of ethanol on TBPS binding does not occur, and the effects of GABA and barbiturates are also unchanged. In contrast to the results with TBPS, chronic ethanol treatment of mice resulted in a reduced ability of pentobarbital, added to assays in vitro, to stimulate BDZ (3-H-Flunitrazepam) (Flu) binding in cortex and cerebellum. Similar results were found in animals that were chronically fed barbiturates. The results support the hypothesis that certain pharmacological effects of ethanol may result from interactions with the GABA-BDZ-barbiturate receptor complex. Chronic treatment with ethanol results in possible adaptive changes that occur at a site other than that originally influenced by ethanol, but that alter the function of the complex as a whole. These biochemical alterations may be associated with various aspects of tolerance, cross-tolerance, and physical dependence on ethanol.