Allan A M, Zhang X, Baier L D
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO 63110.
Brain Res. 1992 Aug 21;588(2):255-60. doi: 10.1016/0006-8993(92)91583-z.
Male ICR mice were fed powdered laboratory chow containing phenobarbital for 7 days to induce tolerance. Mice were sacrificed and brains assayed for changes in GABA-mediated chloride flux into brain membrane vesicles (microsacs). Concentration-dependent stimulation of chloride flux by GABA alone was not affected by the development of tolerance to phenobarbital. Phenobarbital potentiation of GABA-mediated chloride flux was significantly attenuated in the membranes prepared from phenobarbital-tolerant mice compared with those from pair-fed control mice. Similarly, stimulation of GABA-mediated flux by the benzodiazepine, flunitrazepam was also depressed in membranes from tolerant mice. However, the ability of ethanol and the benzodiazepine inverse agonist FG-7142 to modulate GABA-gated chloride flux was not affected by the development of phenobarbital tolerance. No significant changes in saturation [3H]diazepam binding parameters were observed. These findings suggest that there is a degree of cross-tolerance between phenobarbital and benzodiazepine agonist at the level of the GABA-operated chloride channel. Furthermore, although some reports have demonstrated behavioral cross-tolerance between ethanol and barbiturates, the present data suggest different mechanisms of tolerance development for these intoxicants at the level of the GABAA receptor chloride channel complex.
雄性ICR小鼠喂食含苯巴比妥的粉状实验室饲料7天以诱导耐受性。处死小鼠，检测大脑中γ-氨基丁酸（GABA）介导的氯离子流入脑膜囊泡（微囊）的变化。单独GABA对氯离子流入的浓度依赖性刺激不受对苯巴比妥耐受性发展的影响。与配对喂食的对照小鼠相比，苯巴比妥耐受性小鼠制备的膜中，GABA介导的氯离子流入的苯巴比妥增强作用显著减弱。同样，苯二氮䓬类药物氟硝西泮对GABA介导的氯离子流入的刺激在耐受性小鼠的膜中也受到抑制。然而，乙醇和苯二氮䓬类反向激动剂FG-7142调节GABA门控氯离子流入的能力不受苯巴比妥耐受性发展的影响。未观察到饱和[3H]地西泮结合参数有显著变化。这些发现表明，在GABA操作的氯离子通道水平上，苯巴比妥和苯二氮䓬类激动剂之间存在一定程度的交叉耐受性。此外，尽管一些报告显示乙醇和巴比妥类药物之间存在行为交叉耐受性，但目前的数据表明，在GABAA受体氯离子通道复合物水平上，这些毒物的耐受性发展机制不同。
