Yu O, Chiu T H, Rosenberg H C
Department of Pharmacology, Medical College of Ohio, Toledo.
J Pharmacol Exp Ther. 1988 Jul;246(1):107-13.
gamma-Aminobutyric acid (GABA)-gated Cl- influx was studied in rat brain "microsacs." Midazolam caused a shift to the left of the GABA log dose-response curve. Pentobarbital produced a similar shift plus an increase in maximum response. Diazepam, flurazepam and desalkylflurazepam also enhanced GABA-gated Cl- flux. Their effects were blocked by Ro15-1788, a benzodiazepine antagonist. Acute diazepam pretreatment caused a shift to the left of the GABA dose-response curve but had no effect on the ability of benzodiazepines or pentobarbital to increase GABA-gated Cl- influx. In rats made tolerant by 4 weeks of flurazepam treatment, there was no decrease in the ability of GABA to mediate Cl- flux. GABA was more potent in microsacs from nonwithdrawn rats. In rats withdrawn for 12 but not 48 hr, the maximum GABA response was increased. The ability of benzodiazepines and of pentobarbital to enhance GABA-gated Cl- influx was reduced, showing tolerance. However, 2 days after withdrawal from chronic treatment, this was no longer statistically significant. The results show that benzodiazepine tolerance involves reduced functional coupling between the benzodiazepine recognition site and the GABA recognition site-Cl- channel. Furthermore, reduced effectiveness of GABAA agonists in benzodiazepine-tolerant animals might result from alterations in neuronal activity that occur subsequently to activation of the GABA receptor-gated anion channel.
在大鼠脑“微囊”中研究了γ-氨基丁酸（GABA）门控的氯离子内流。咪达唑仑使GABA对数剂量反应曲线向左移位。戊巴比妥产生类似的移位并使最大反应增加。地西泮、氟西泮和去烷基氟西泮也增强了GABA门控的氯离子通量。它们的作用被苯二氮䓬拮抗剂Ro15 - 1788阻断。急性地西泮预处理使GABA剂量反应曲线向左移位，但对苯二氮䓬或戊巴比妥增加GABA门控的氯离子内流的能力没有影响。在用氟西泮治疗4周产生耐受性的大鼠中，GABA介导氯离子通量的能力没有降低。GABA在未撤药大鼠的微囊中更有效。在撤药12小时而非48小时的大鼠中，GABA的最大反应增加。苯二氮䓬和戊巴比妥增强GABA门控的氯离子内流的能力降低，表现出耐受性。然而，在慢性治疗撤药2天后，这在统计学上不再显著。结果表明，苯二氮䓬耐受性涉及苯二氮䓬识别位点与GABA识别位点 - 氯离子通道之间功能偶联的降低。此外，在苯二氮䓬耐受的动物中，GABAA激动剂有效性降低可能是由于GABA受体门控阴离子通道激活后发生的神经元活动改变所致。
