Barbiturate tolerance: effects on GABA-operated chloride channel function.
Barbiturate tolerance: effects on GABA-operated chloride channel function.
复制标题
巴比妥耐受性：对 GABA 操作的氯离子通道功能的影响。
DOI：
10.1016/0006-8993(92)91583-z
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发表时间：
1992
期刊：
影响因子：
2.9
通讯作者：
Baier,LD
中科院分区：
文献类型：
--
作者：
Allan,AM;Zhang,X;Baier,LD
用含苯巴比妥粉的实验饲料喂养雄性ICR小鼠7d，诱导耐受。处死小鼠，检测大脑中GABA介导的氯离子流入膜小泡(微囊)的变化。单独使用GABA对氯离子通量的浓度依赖性刺激不受苯巴比妥耐受发展的影响。在苯巴比妥耐受小鼠制备的膜中，与配对喂养的对照小鼠相比，苯巴比妥对GABA介导的氯离子通量的增强作用显著减弱。类似地，苯二氮类药物氟硝西潘对GABA介导的通量的刺激也被抑制在耐受小鼠的细胞膜上。然而，乙醇和苯二氮卓类反向激动剂FG-7142调节GABA门控氯离子通量的能力不受苯巴比妥耐受性的影响。未观察到饱和度[~3H]地西潘结合参数的显著变化。这些发现表明，苯巴比妥和苯二氮卓类激动剂在GABA操作的氯离子通道水平上存在一定程度的交叉耐受。此外，尽管一些报告显示了乙醇和巴比妥酸盐之间的行为交叉耐受，但目前的数据表明，在GABA受体氯通道复合体水平上，这些毒物的耐受发展机制不同。
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 membrane vesicles (microsacs). Concentration-dependent stimulation of chloride flux by GABA alone was not affected by the development of tolerance of 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 GABAAreceptor chloride channel complex.