R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: An in vivo microdialysis and receptor binding study
R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: An in vivo microdialysis and receptor binding study
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DOI：
10.1016/s0893-133x(02)00377-9
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发表时间：
2002-12-01
影响因子：
7.6
通讯作者：
Bymaster, FP
中科院分区：
文献类型：
--
作者：
Koch, S;Perry, KW;Bymaster, FP
选择性5-羟色胺再摄取抑制剂氟西汀由等量的R和S异构体组成。在这项研究中，我们通过转运体和受体结合分析以及在自由活动的大鼠体内微透析来研究立体异构体的药理学特性。与转运体的结合证实了R-和S-氟西汀对5-羟色胺转运体相对于多巴胺(DA)和去甲肾上腺素(NE)人转运体的选择性。受体结合研究表明，R-氟西汀对人5-HT2A和5-HT2C受体亚型有显著的亲和力，而S-氟西汀则不然。功能性GTP-GammaS结合研究表明，R-氟西汀是5-HT2A和5-HT2C受体的拮抗剂。在微透析研究中，急性R-氟西汀和S-氟西汀增加了前额叶皮质细胞外5-羟色胺、多巴胺和去甲肾上腺素的水平，但R-氟西汀引起的儿茶酚胺的增加更明显。R-氟西汀增加前额叶、伏隔核和下丘脑的5-羟色胺和去甲肾上腺素的细胞外水平，增加前额叶和下丘脑的多巴胺，但不增加富含多巴胺的伏隔核和纹状体的多巴胺的水平，这可能是一种区域选择性作用。选择性5-羟色胺摄取抑制剂R-氟西汀对细胞外儿茶酚胺的意外增加可能是由于其对5-HT2C受体的拮抗作用。(C)2002年美国神经精神药理学学院。爱思唯尔科学公司出版。
The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S sterevisomers. In this study, we investigated the pharmacologic properties of the stereoisomers using transporter and receptor binding assays and in vivo microdialysis in freely moving rats. Binding to the transporter confirmed selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine (DA) and norepinephrine (NE) human transporters. Receptor binding studies demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for human 5-HT2A and 5-HT2C receptor subtypes. Functional GTPgammaS binding studies indicated that R-fluoxetine is an antagonist at 5-HT2A and 5-HT2C receptors. In microdialysis studies, acute R- and S-fluoxetine increased extracellular levels of 5-HT, DA, and NE in prefrontal cortex (PFC), but R-fluoxetine caused significantly greater increases of catecholamines. R-fluoxetine increased extracellular levels of 5-HT and NE in PFC, nucleus accumbens, and hypothalamus, whereas it increased dopainine in PFC and hypothalamus, but not in DA-rich nucleus accumbens and striatum, thus indicating a regionally selective effect. The unexpected increases of extracellular catecholamines by a selective 5-HT uptake inhibitor like R-fluoxetine may be due to its antagonism of 5-HT2C receptors. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.