Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids
Fluoxetine and norfluoxetine stereospecifically facilitate pentobarbital sedation by increasing neurosteroids
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DOI：
10.1073/pnas.0401479101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Guidotti, A
中科院分区：
文献类型：
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作者：
Pinna, G;Costa, E;Guidotti, A
被安置在社会隔离中的小鼠对伽马氨基丁酸模拟药物[即戊巴比妥(PTB)]的反应降低，与端脑别孕酮(Allo)水平下调有关。在这些小鼠中，肺结核引起的翻正反射的丧失大大减少。氟西汀(Floxetine，Flx)和去氟西汀(Norfloxetine，NFlx)立体特异性地逆转了社会隔离对PTB引起的翻正反射丧失和端脑Allo含量降低的影响。氟尿嘧啶和诺氟沙星的S异构体的效力分别是它们各自的R-异构体的2倍和7倍。氟尿嘧啶和诺氟沙星对脑组织ALTO含量和PTB作用所需的EC(50)S比选择性5-羟色胺再摄取抑制剂活性所需的IC(50)S低10-50倍。我们的结论是，氟尿嘧啶和氟尿嘧啶的S异构体引起的PTB作用的正常化与逆转脑内ALLO含量的下调有关，并且不依赖于选择性5-羟色胺再摄取抑制物的活性。
Mice housed in social isolation exhibit a decreased response to gamma-aminobutyric acid-mimetic drugs [i.e., pentobarbital (PTB)] associated with a down-regulation of telencephalic allopregnanolone (Allo) levels. In these mice, the PTB-induced loss of righting reflex is greatly reduced. Fluoxetine (FLX) and norfluoxetine (NFLX) stereospecifically reverse the effect of social isolation on the PTB-induced loss of righting reflex and on the decrease of telencephalic Allo content. The S-isomers of FLX and NFLX are 2- and 7-fold more potent, respectively, than their respective R-isomers. The EC(50)s of FLX and NFLX required to normalize brain Alto content and PTB action are 10-50 times lower than the IC(50)s required for selective serotonin reuptake inhibitor activity. We conclude that normalization of PTB action elicited by the S-isomers of FLX and NFLX is related to the reversal of the down-regulation of brain Allo content and is independent of selective serotonin reuptake inhibitor activity.