Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABA_A receptor subtypes in mice

详细信息	查看全文 | 推荐本文 |

• 作者：Kiersten S. Smith^a ; ^c ; ¹ ; Elif Engin^a ; ^c ; ¹ ; ^{eengin@mclean.harvard.edu} ; Edward G. Meloni^b ; ^c ; Uwe Rudolph^a ; ^c
• 关键词：GABAA receptor ; 伪 subunit ; Anxiety ; Conditioned fear ; Benzodiazepine ; Fear-potentiated startle
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：August, 2012
• 卷：63
• 期：2
• 页码：250-258
• 文件大小：663 K

摘要

GABA_A receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA_A receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA_A receptor subtypes by challenging wild type, 伪1(H101R), 伪2(H101R) and 伪3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, 伪1(H101R) and 伪3(H126R), but this effect was abolished in 伪2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and 伪3(H126R) mice, the fear-reducing effects of these drugs were absent in both 伪1(H101R) and 伪2(H101R) point mutants, indicating that both 伪1- and 伪2-containing GABA_A receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA_A receptor subtype requirements for the impact of BZs, specifically that both 伪1- and 伪2-containing GABA_A receptors are necessary for BZs to reduce conditioned fear whereas only 伪2-containing GABA_A receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.