Nguyen Q, Sapp D W, Van Ness P C, Olsen R W
Department of Molecular & Medical Pharmacology, School of Medicine, University of California, Los Angeles 90024, USA.
Synapse. 1995 Feb;19(2):77-87. doi: 10.1002/syn.890190203.
Allosteric modulation by neuroactive steroids of radioligand binding sites on the GABAA receptor complex was demonstrated by autoradiography in vitro in several regions of human brain and the effects compared to those in rat brain. Comparing human and rat, two steroids known to be active in enhancing GABA-mediated postsynaptic inhibition, 5 alpha-pregnane-3 alpha,21-diol-20-one (tetrahydro-deoxycorticosterone, THDOC) and alphaxalone (5 alpha-pregnane-3 alpha-hydroxy-11,20-dione), allosterically inhibited [35S]T-BPS binding to the picrotoxin/convulsant site in both species in several regions including the hippocampus. Unlike rat, human brain binding of [3H]flunitrazepam to the benzodiazepine site was not enhanced by alphaxalone (at any concentration), but was unaffected in many regions and inhibited in others. Binding of [3H]muscimol to high and low affinity GABA sites were enhanced by both steroids in all tested regions of rat brain, although to varying degrees. However, several lobes of human cortex showed no modulation of muscimol binding by either steroid, and THDOC, but not alphaxalone, inhibited in some areas. Comparing regions, THDOC at high concentrations (10 microM) enhanced in human frontal lobe and primary sensory and motor cortex, with greater effect in deep layers than superficial. This steroid had no effect in other parts of parietal lobe and inhibited muscimol binding in temporal lobe, primary visual cortex, and other parts of occipital lobe. Concentration-dependence curves for THDOC showed regional variation, e.g., in the hippocampal formation and surrounding neocortex. These regional and species differences are consistent with the existence of multiple GABAA receptor subtypes that differ in pharmacology. This heterogeneity provides both the opportunity and the difficulty of targeting clinically useful medications such as antiepileptic drugs to the appropriate human brain regions, and the species differences in regional subtype expression suggest caution in use of animal models.
通过体外放射自显影技术，在人类大脑的几个区域证实了神经活性甾体对GABAA受体复合物上放射性配体结合位点的变构调节作用，并与大鼠大脑中的作用进行了比较。比较人类和大鼠，两种已知能增强GABA介导的突触后抑制作用的甾体，5α-孕烷-3α,21-二醇-20-酮（四氢脱氧皮质酮，THDOC）和阿法沙龙（5α-孕烷-3α-羟基-11,20-二酮），在包括海马体在内的几个区域，均变构抑制了两种物种中[35S]T-BPS与印防己毒素/惊厥位点的结合。与大鼠不同，阿法沙龙（在任何浓度下）均未增强人类大脑中[3H]氟硝西泮与苯二氮䓬位点的结合，在许多区域未受影响，而在其他区域则受到抑制。在大鼠大脑的所有测试区域，两种甾体均增强了[3H]蝇蕈醇与高亲和力和低亲和力GABA位点的结合，尽管程度不同。然而，人类大脑皮层的几个叶均未显示出任何一种甾体对蝇蕈醇结合的调节作用，并且THDOC（而非阿法沙龙）在某些区域具有抑制作用。比较不同区域，高浓度（10μM）的THDOC增强了人类额叶以及初级感觉和运动皮层的结合，对深层的作用大于浅层。该甾体在顶叶的其他部分没有作用，并且抑制了颞叶、初级视觉皮层和枕叶其他部分的蝇蕈醇结合。THDOC的浓度依赖性曲线显示出区域差异，例如在海马结构和周围新皮层中。这些区域和物种差异与存在药理学上不同的多种GABAA受体亚型一致。这种异质性既为将抗癫痫药物等临床有用药物靶向至合适的人类大脑区域提供了机会，也带来了困难，并且区域亚型表达的物种差异提示在使用动物模型时应谨慎。
