Squires R F, Saederup E
The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Neurochem Res. 1998 Oct;23(10):1283-90. doi: 10.1023/a:1020796200769.
Clozapine and several other antipsychotic/antidepressant drugs that fully or partially block GABA(A) receptors were tested at concentrations that reversed the inhibitory effect of 1 microM GABA on 35S-t-butylbicyclophosphorothionate ([35S]TBPS) binding to rat forebrain membranes only about 20-30%, here designated "core" fractions. Clozapine at 10 microM reverses 1 microM GABA 25+/-4.0% (n = 23) (its "core" fraction). Fourty three compounds were tested alone, and pairwise together with 10 microM Clozapine. The "core" fractions of some of the compounds yielded significant additive reversals together with 10 microM Clozapine, while others did not. A group of 14 compounds of which 7 are clinically effective antipsychotic drugs, including Chlorprothixene, Clomacran, Clopipazan, Fluotracen, Sulforidazine, Thioproperazine, and cis-Thiothixene, were statistically non-additive with 10 microM Clozapine, suggesting that all of these drugs selectively block the same core population of GABA(A) receptors as Clozapine. These non-additivities also suggest that Clozapine at 10 microM fully saturates a subset of GABA(A) receptors blocked by 1 microM GABA. Therefore, Clozapine probably blocks 2 or more types of GABA(A)receptors, but only half of the receptors that are sensitive to 1 microM GABA. A second group of 12 compounds of which 6 are clinically active antidepressant/antipsychotic drugs including Amoxapine, Clothiapine, Dibenzepine, Inkasan (Metralindole), Metiapine and Zimelidine were slightly, but significantly, additive with Clozapine suggesting that these compounds block most of Clozapine's core fraction, plus a small additional fraction. A third group consisted of ten compounds that yielded larger (R > 80) and statistically highly significant additivities with Clozapine. Complete additivity was obtained with Bathophenanthroline disulfonate, and Isocarboxazid, suggesting that they block GABA(A) receptors other than those blocked by 10 microM Clozapine. Seven "classical" GABA(A) receptor blockers, also tested at concentrations yielding 21 to 33% reversal alone, were all significantly additive with 10 microM Clozapine, but in no case was the additivity complete. The largest additivity was obtained with Pitrazepine (21%) and the smallest with Tubocurarine (9%). These results provide further support for the notion that selective blockade of the same subset of GABA(A) receptors may contribute to the clinical antipsychotic/antidepressant effects of Clozapine. The deltaB(opt) values for Clozapine are 50+/-1.7% and 26+/-2.6% (n = 3) in whole rat forebrain and cerebellum, respectively, confirming that clozapine-sensitive GABA(A) receptors are unevenly distributed in the brain. The sedative and anxiolytic properties of Clozapine and other antipsychotic drugs may be due to selective blockade of GABergic disinhibition at certain interneurons.
氯氮平和其他几种能完全或部分阻断GABA(A)受体的抗精神病/抗抑郁药物，在能逆转1微摩尔GABA对35S-叔丁基双环磷硫代酸盐（[35S]TBPS）与大鼠前脑细胞膜结合的抑制作用的浓度下进行测试，此处将其称为“核心”部分，这种逆转作用仅为20%-30%左右。10微摩尔的氯氮平能逆转1微摩尔GABA作用的25±4.0%（n = 23）（其“核心”部分）。单独测试了43种化合物，并将它们与10微摩尔氯氮平两两组合进行测试。一些化合物的“核心”部分与10微摩尔氯氮平一起产生了显著的相加逆转作用，而其他化合物则没有。一组14种化合物，其中7种是临床有效的抗精神病药物，包括氯普噻吨、氯麦角林、氯哌嗪、氟托拉嗪、舒必利、硫丙嗪和顺式硫利达嗪，与10微摩尔氯氮平在统计学上无相加作用，这表明所有这些药物与氯氮平选择性地阻断相同的GABA(A)受体核心群体。这些非相加性还表明，10微摩尔的氯氮平使1微摩尔GABA阻断的GABA(A)受体亚群完全饱和。因此，氯氮平可能阻断2种或更多类型的GABA(A)受体，但仅阻断对1微摩尔GABA敏感的受体的一半。第二组12种化合物，其中6种是临床有效的抗抑郁/抗精神病药物，包括阿莫沙平、氯噻平、二苯氮䓬、因卡桑（美曲吲哚）、甲硫平和平咪嗪，与氯氮平有轻微但显著的相加作用，这表明这些化合物阻断了氯氮平的大部分核心部分，再加上一小部分额外部分。第三组由10种化合物组成，它们与氯氮平产生了更大（R > 80）且在统计学上高度显著的相加作用。二磺酸 bathophenanthroline 和异卡波肼产生了完全相加作用，这表明它们阻断的GABA(A)受体不同于10微摩尔氯氮平所阻断的受体。7种“经典”的GABA(A)受体阻断剂，也在单独产生21%至33%逆转作用的浓度下进行了测试，它们与10微摩尔氯氮平均有显著的相加作用，但相加作用均不完全。皮他西泮（21%）的相加作用最大，筒箭毒碱（9%）的相加作用最小。这些结果进一步支持了这样一种观点，即选择性阻断同一亚群的GABA(A)受体可能有助于氯氮平的临床抗精神病/抗抑郁作用。氯氮平在整个大鼠前脑和小脑中的deltaB(opt)值分别为50±1.7%和26±2.6%（n = 3），证实了对氯氮平敏感地GABA(A)受体在脑中分布不均。氯氮平和其他抗精神病药物的镇静和抗焦虑特性可能是由于在某些中间神经元处选择性阻断了GABA能去抑制作用。
