Sedative but not anxiolytic properties of benzodiazepines ave mediated by the GABAA receptor α1 subtype
Sedative but not anxiolytic properties of benzodiazepines ave mediated by the GABAA receptor α1 subtype
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DOI：
10.1038/75761
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发表时间：
2000-06-01
影响因子：
25
通讯作者：
Whiting, PJ
中科院分区：
文献类型：
--
作者：
McKernan, RM;Rosahl, TW;Whiting, PJ
脑内抑制性神经传递在很大程度上由GABA(A)受体介导。通过变构的苯二氮卓(BZ)位点增强GABA受体的激活，可以产生临床使用的BZS(如安定)的镇静、缓解焦虑、肌肉松弛、抗惊厥和认知障碍的作用。我们创建了具有安定不敏感的α(1)亚型和选择性BZ位点配体L-838,417的转基因小鼠(α(1)H101R)，以探索介导特定生理效应的GABAA(A)受体亚型。这两种互补的方法表明，α(1)亚型介导了苯二氮卓类的镇静作用，但不是缓解焦虑的作用。这一发现提出了改进抗焦虑药物的方法，并基于它们对不同神经元回路中GABA(A)受体亚型的特异性，开发治疗其他神经疾病的药物。
GInhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha(1) H101R) with a diazepam-insensitive alpha(1) subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha(1) subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.