Schmid L, Bottlaender M, Brouillet E, Fuseau C, Mazière M
Service Hospitalier Frédéric Joliot, Centre National de la Recherche Scientifique Unité de Recherche Associée, Orsay, France.
J Pharmacol Exp Ther. 1996 Mar;276(3):977-83.
The influence of increased endogenous gamma-aminobutyric acid (GABA) concentrations on benzodiazepine receptor (BZR) function was studied in the living baboon brain. By using positron emission tomography and the radiotracer [11C] flumazenil combined with electroencephalography, the anticonvulsant/proconvulsant activity and the potency of the BZR agonist diazepam and the inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM), a beta-carboline, were determined in baboons pretreated or not with 500mg/kg of vigabatrin (irreversible inhibitor of the GABA-aminotransferase which increases GABA concentrations in vivo). Pretreatment with vigabatrin increased the threshold of paroxysmal pentylenetetrazol-induced seizure. In both vigabatrin-treated and -untreated animals, the threshold dose of pentylenetetrazol increased with increasing doses of diazepam; it decreased with increasing doses of beta-CCM. The proconvulsant activity of beta-CCM was at all doses reduced in vigabatrin-treated animals compared to untreated animals, whereas, surprisingly, the anticonvulsant activity of high doses of diazepam was reduced after vigabatrin. The potency of diazepam in displacing [11C] flumazenil was enhanced in vigabatrin-pretreated animals, contrasting with the reduced anticonvulsant effects of diazepam in those animals. We determined the linear relationship between the fractional receptor occupancy and the anticonvulsant/proconvulsant effect. The slope, an estimate of the intrinsic efficacy of a BZR ligand, was reduced markedly for diazepam after vigabatrin pretreatment, whereas that for beta-CCM was unmodified. This indicates that increasing GABA levels in vivo reduce the anticonvulsant activity of the BZR agonist diazepam by decreasing its intrinsic efficacy, whereas the intrinsic efficacy of the inverse agonist beta-CCM remains essentially unaltered.
在活体狒狒大脑中研究了内源性γ-氨基丁酸（GABA）浓度升高对苯二氮䓬受体（BZR）功能的影响。通过正电子发射断层扫描和放射性示踪剂[11C]氟马西尼并结合脑电图，在预先用或未用500mg/kg氨己烯酸（一种不可逆的GABA转氨酶抑制剂，可在体内增加GABA浓度）预处理的狒狒中，测定了BZR激动剂地西泮和反向激动剂β-咔啉-3-羧酸甲酯（β-CCM，一种β-咔啉）的抗惊厥/促惊厥活性及效能。用氨己烯酸预处理可提高戊四氮诱发癫痫发作的阈值。在氨己烯酸处理和未处理的动物中，戊四氮的阈值剂量均随地西泮剂量增加而升高；随β-CCM剂量增加而降低。与未处理动物相比，氨己烯酸处理动物中β-CCM在所有剂量下的促惊厥活性均降低，然而，令人惊讶的是，高剂量地西泮的抗惊厥活性在氨己烯酸处理后降低。在氨己烯酸预处理的动物中，地西泮置换[11C]氟马西尼的效能增强，这与地西泮在这些动物中抗惊厥作用降低形成对比。我们确定了受体占有率分数与抗惊厥/促惊厥效应之间的线性关系。斜率是BZR配体内在效能的一个估计值，氨己烯酸预处理后地西泮的斜率显著降低，而β-CCM的斜率未改变。这表明体内GABA水平升高通过降低其内在效能来降低BZR激动剂地西泮的抗惊厥活性，而反向激动剂β-CCM的内在效能基本保持不变。
