Ormandy G C, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294.
Brain Res. 1991 Jul 5;553(1):51-7. doi: 10.1016/0006-8993(91)90229-o.
Previous studies with lithium have shown that it potentiated the in vivo response to cholinomimetics in rats, resulting in seizures at otherwise non-convulsant doses, but did not affect seizure activity induced by a number of chemical convulsants including kainic acid and N-methyl-D-aspartate (NMDA). In vitro experiments have suggested that lithium interferes with receptor-mediated second messenger production, possibly due to an action at G-proteins. The present study tested the hypothesis that selective inhibition of G-proteins by in vivo administration of pertussis toxin would induce effects similar to those of lithium. The results reported here demonstrate that pertussis toxin mimics lithium in potentiating the convulsant response to pilocarpine in rats. The effect of pertussis toxin was dose-dependent and the extent of potentiation was over 13-fold, which was remarkably similar to lithium. The seizures were prevented by pretreatment with atropine, phenobarbital or diazepam. L-Phenylisopropyladenosine (L-PIA) and MK-801 also demonstrated anticonvulsant activity, with MK-801 also protecting the rats against the rapid death associated with pertussis toxin/pilocarpine-induced seizures. Thus, seizures were cholinergically initiated and were controlled by the same drugs as were lithium/pilocarpine-induced seizures. The results illustrate that in several respects the response to cholinomimetics is modified in a similar manner by lithium and pertussis toxin. However, pertussis toxin lacks the specificity of lithium as it also potentiated the convulsant effects of kainic acid and NMDA.
先前对锂的研究表明，它能增强大鼠体内对拟胆碱药的反应，在原本非惊厥剂量下引发癫痫发作，但不影响由多种化学惊厥剂（包括 kainic 酸和 N-甲基-D-天冬氨酸（NMDA））诱导的癫痫活动。体外实验表明，锂可能通过作用于 G 蛋白干扰受体介导的第二信使生成。本研究检验了一个假设，即通过体内注射百日咳毒素选择性抑制 G 蛋白会产生与锂类似的效果。此处报告的结果表明，百日咳毒素在增强大鼠对毛果芸香碱的惊厥反应方面模拟了锂的作用。百日咳毒素的作用呈剂量依赖性，增强程度超过 13 倍，这与锂非常相似。用阿托品、苯巴比妥或地西泮预处理可预防癫痫发作。L-苯基异丙基腺苷（L-PIA）和 MK-801 也表现出抗惊厥活性，MK-801 还能保护大鼠免于百日咳毒素/毛果芸香碱诱导的癫痫发作相关的快速死亡。因此，癫痫发作由胆碱能引发，且由与锂/毛果芸香碱诱导的癫痫发作相同的药物控制。结果表明，在几个方面，锂和百日咳毒素以类似方式改变了对拟胆碱药的反应。然而，百日咳毒素缺乏锂的特异性，因为它也增强了 kainic 酸和 NMDA 的惊厥作用。
