In vivo occupancy of female rat brain estrogen receptors by 17脙脙脙脙-estradiol and tamoxifen

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• 作者：Pareto ; D. ; Alvarado ; M. ; Hanrahan ; S.M. ; Biegon ; Anat
• 关键词：SERMs ; 16脦脦-[¹⁸F]fluoroestradiol ; 11脦脦-Methoxy-16脦脦-[¹²⁵I]iodo-estradiol ; Autoradiography
• 刊名：Neuroimage
• 出版年：2004
• 期刊代码：83_10538119
• 类别：neu
• 出版时间：November, 2004
• 卷：23
• 期：3
• 页码：1161-1167
• 文件大小：305 K

摘要

Estrogens or antiestrogens are currently used by millions of women, but the interaction of these hormonal agents with brain estrogen receptors (ER) in vivo has not been characterized to date. Our goal was to assess, in vivo, the extent and regional distribution of brain ER occupancy in rats chronically exposed to 17脦脦-estradiol (E₂) or tamoxifen (TAM). For that purpose, female ovariectomized Sprague脦脦脦Dawley rats were implanted with subcutaneous pellets containing either placebo (OVX), E₂, or TAM for 3 weeks. ER occupancy in grossly dissected regions was quantified with 16脦脦-[¹⁸F]fluoroestradiol ([¹⁸F]FES). Both E₂ and TAM produced significant decreases in radioligand uptake in the brain although the effect of E₂ was larger and more widespread than the effect of TAM. Detailed regional analysis of the interaction was then undertaken using a radioiodinated ligand, 11脦脦-methoxy-16脦脦-[¹²⁵I]iodo-estradiol ([¹²⁵I]MIE₂), and quantitative ex vivo autoradiography. E₂ treatment resulted in near-complete (86.6 脦脦 17.5%) inhibition of radioligand accumulation throughout the brain, while ER occupancy in the TAM group showed a marked regional distribution such that percentage inhibition ranged from 40.5 脦脦 15.6 in the ventrolateral part of the ventromedial hypothalamic nucleus to 84.6 脦脦 4.5 in the cortical amygdala. These results show that exposure to pharmacologically relevant levels of TAM produces a variable, region-specific pattern of brain ER occupancy, which may be influenced by the regional proportion of ER receptor subtypes. These findings may partially explain the highly variable and region-specific effects observed in neurochemical, metabolic, and functional studies of the effects of TAM in the brain of experimental animals as well as human subjects.