Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice
Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice
复制标题
DOI：
10.1124/jpet.109.158717
复制
发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Lucki, Irwin
中科院分区：
文献类型：
--
作者：
Hodes, Georgia E.;Hill-Smith, Tiffany E.;Lucki, Irwin
神经发生是抗抑郁药产生治疗效果的一种机制。关于抗抑郁药对女性神经发生和神经营养因子动员的影响的信息缺乏。这项研究考察了大脑多个区域中细胞增殖和存活改变的性别差异。另外的实验检查了脑源性神经营养因子（BDNF）水平和氟西汀的药代动力学，以确定它们是否介导性别差异。MRL/MpJ小鼠分别给予氟西汀（5和10 mg/kg）治疗21 d，并注射5-溴-2'-脱氧尿苷（200 mg/kg）测定DNA合成。在海马中，两种剂量的氟西汀都增加了细胞增殖；10 mg/kg处理的雌性比雄性产生更多的新细胞。氟西汀不会改变雄性的存活率，但10 mg/kg的氟西汀会降低雌性的存活率。在额叶皮质中，氟西汀增加了10 mg/kg雄性小鼠的细胞增殖和存活。在小脑和杏仁核中，10 mg/kg氟西汀增加了两性细胞的增殖，但没有改变新细胞的合并。氟西汀增加了两性海马区的BDNF水平。BDNF水平与男性细胞增殖相关，而与女性无关。脑和血浆水平表明，女性比男性更快地代谢氟西汀，并产生更多的代谢物去甲氟西汀。这些数据表明，氟西汀作用于大脑的多个区域，以增加细胞增殖，并且激活模式在男性和女性之间有所不同。氟西汀对神经营养因子动员和药代动力学的性别特异性影响可能有助于神经可塑性的这些差异。
Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2'-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity.