Squires R F, Saederup E
The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.
Neurochem Res. 1997 Feb;22(2):151-62. doi: 10.1023/a:1027359422433.
Selective blockade of a subset of GABA(A) receptors may be involved in the antipsychotic effects of Clozapine and several other antipsychotic drugs. Seven antipsychotic drugs, and 11 drugs classified as antidepressants that only partially reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, do not yield additive reversal when tested pairwise with Clozapine, which also only partially reverses the inhibitory effect of GABA. This suggests that all of these antipsychotic/antidepressant drugs may block a common subset of GABA(A) receptors. DMCM and Ro 5-4864 are also partial reversers of GABA's inhibitory effect, but they yield additive reversals when tested pairwise with the antipsychotic/antidepressant drugs, and also with each other, suggesting that DMCM, Ro 5-4864, and the antipsychotic drugs define three heterogeneous subsets of GABA(A) receptors, with variable overlap, depending on the drug. Several potent ligands for benzodiazepine binding sites can block the GABA inhibitory effects of DMCM and Ro 5-4864, but with different patterns: the ligands generally blocked DMCM less potently, but more completely than Ro 5-4864. Ro 5-4864 was not blocked by Flumazenil or CGS-8216, ligands that potently blocked DMCM. Nine additional antipsychotic/antidepressant drugs, as well as Clozapine, and 7 "classical" GABA(A) receptor blockers, all of which reversed GABA nearly completely, when tested at lower concentrations that only reverse approximately 20-35%, yielded almost complete additivity when tested pairwise with DMCM or Ro 54864. Another convulsant benzodiazepine, KW-1937, a positional isomer of Brotizolam, fully reverses the inhibitory effect of 1 microM GABA. At a lower concentration yielding about 50% reversal, KW-1937 is completely additive with DMCM, but entirely nonadditive with Ro 5-4864. The 50% reversal obtained with KW-1937 was potently blocked by Triazolam, but with a plateau similar to that obtained with Ro 5-4864. The results with KW- 1937 suggest that its 50% reversal largely corresponds to the reversal obtained with Ro 5-4864, and that virtually all of the [35S]TBPS binding sites inhibited by 1 microM GABA are coupled to benzodiazepine binding sites. The fraction of GABA(A) receptors preferentially blocked by all the antipsychotic/antidepressant drugs, roughly 25% of the [35S]TBPS binding sites inhibited with 1 microM GABA, are sensitive to KW-1937, but not to DMCM or to Ro 5-4864.
对GABA(A)受体亚群的选择性阻断可能与氯氮平和其他几种抗精神病药物的抗精神病作用有关。七种抗精神病药物以及11种被归类为仅部分逆转1微摩尔GABA对[35S]TBPS结合抑制作用的抗抑郁药物，与氯氮平两两测试时不会产生相加性逆转，氯氮平也只是部分逆转GABA的抑制作用。这表明所有这些抗精神病/抗抑郁药物可能阻断GABA(A)受体的一个共同亚群。DMCM和Ro 5-4864也是GABA抑制作用的部分逆转剂，但它们与抗精神病/抗抑郁药物两两测试时以及相互测试时会产生相加性逆转，这表明DMCM、Ro 5-4864和抗精神病药物定义了GABA(A)受体的三个异质亚群，重叠程度各不相同，取决于药物。几种苯二氮䓬结合位点的强效配体可以阻断DMCM和Ro 5-4864的GABA抑制作用，但模式不同：这些配体通常对DMCM的阻断效力较弱，但比对Ro 5-4864的阻断更完全。Ro 5-4864不会被氟马西尼或CGS-8216阻断，而这两种配体可有效阻断DMCM。另外九种抗精神病/抗抑郁药物以及氯氮平，还有7种“经典”GABA(A)受体阻断剂，在较低浓度下测试时，它们几乎能完全逆转GABA的抑制作用，而在该浓度下它们只能逆转约20-35%的抑制作用，与DMCM或Ro 54864两两测试时几乎产生完全相加性。另一种惊厥性苯二氮䓬KW-1937，是溴替唑仑的位置异构体，能完全逆转1微摩尔GABA的抑制作用。在产生约50%逆转的较低浓度下，KW-1937与DMCM完全相加，但与Ro 5-4864完全无相加性。KW-1937产生的50%逆转被三唑仑有效阻断，但呈现出与Ro 5-4864相似的平台期。KW-1937的结果表明，其50%的逆转在很大程度上与Ro 5-4864产生的逆转相对应，并且几乎所有被1微摩尔GABA抑制的[35S]TBPS结合位点都与苯二氮䓬结合位点偶联。所有抗精神病/抗抑郁药物优先阻断的GABA(A)受体部分，大约是被1微摩尔GABA抑制的[35S]TBPS结合位点的25%，对KW-1937敏感，但对DMCM或Ro 5-4864不敏感。
