Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
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DOI：
10.1038/44579
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发表时间：
1999-10-21
期刊：
影响因子：
64.8
通讯作者：
Möhler, H
中科院分区：
文献类型：
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作者：
Rudolph, U;Crestani, F;Möhler, H
GABA（A）（γ-氨基丁酸（A））受体是用于调节警觉、焦虑、肌肉紧张、致癫痫活动和记忆功能的分子底物，这从作用于其调节性苯二氮卓结合位点的临床有效药物引起的作用谱中显而易见。在这里，我们表明，通过在小鼠α 1亚基基因的101位引入组氨酸到精氨酸的点突变，主要在皮质区和丘脑中表达的α 1型GABA（A）受体（1）对苯二氮卓位点配体的变构调节不敏感，而生理性神经递质γ-氨基丁酸的调节得以保留。α 1（H101 R）小鼠不能显示安定的镇静、遗忘和部分抗惊厥作用。相比之下，抗焦虑、肌松、运动障碍和乙醇增强作用完全保留，这归因于在边缘系统（α 2，α 5）、单胺能神经元（α 3）和运动神经元（α 2，α 5）中发现的非突变GABA（A）受体（1）。因此，苯二氮卓诱导的行为反应是由不同神经元回路中的特定GABA（A）受体亚型介导的，这对于药物设计是有意义的。
GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha 1-subunit gene, that alpha 1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus(1), are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha 1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha 2, alpha 5), in monoaminergic neurons (alpha 3) and in motoneurons (alpha 2, alpha 5)(1). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.