5-HT transporter function: Interaction of antidepressants and hormones

5-HT 转运蛋白功能：抗抑郁药和激素的相互作用

• 批准号: 8073658
• 负责人: ALAN FRAZER
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073658
• 关键词: Acute; Agonist; Antidepressive Agents; Behavior; Behavioral; Biotinylation; Brain; Brain-Derived Neurotrophic Factor; Cell membrane; Chronic; Dose; Estradiol; Estradiol Benzoate; Estrogen Nuclear Receptor; Estrogen Receptors; Estrogens; Female; Fluvoxamine; Genomics; Goals; Gonadal Steroid Hormones; Heterozygote; Hippocampus (Brain); Hormonal; Hormones; In Situ; K 252a; Knockout Mice; Major Depressive Disorder; Measures; Mediating; Membrane; Menopause; Metabolic Clearance Rate; Microdialysis; Modeling; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear Receptors; Ovarian; Ovarian hormone; Phosphorylation; Postpartum Depression; Postpartum Period; Pregnancy; Progesterone; Pseudopregnancy; Rattus; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signaling Molecule; Simulate; Steroids; Surface; Swimming; Techniques; Testing; Time; Withdrawal; Woman; World Health Organization; base; burden of illness; cellular targeting; extracellular; in vivo; men; neurochemistry; non-genomic; prevent; public health relevance; receptor; reproductive; research study; serotonin transporter

DESCRIPTION (provided by applicant): The vulnerability of some women to develop major depressive disorder (MDD), which occurs more frequently in women than in men, is associated with hormonal fluctuations (monthly, pregnancy, postpartum, and menopause). We have shown recently, using the technique of in vivo chronoamperometry, that acute administration of ovarian hormones (estradiol benzoate (EB) or progesterone (P)) impacts the ability of selective serotonin reuptake inhibitors (SSRIs) to alter the function of what is widely considered their initial cellular target in brain - the serotonin transporter (SERT). In addition, EB but not P, when given acutely, blocked SERT function as demonstrated by a diminished clearance of exogenously applied serotonin. Thus, EB has two actions. On its own, it slows the clearance of 5-HT, an effect similar to that caused by SSRIs. One might speculate that estrogen is antidepressant based on such an effect. However, we also find estrogen to interfere with the ability of SSRIs to slow 5-HT clearance. Such an effect might be expected to compromise the antidepressant effects of SSRIs. Estrogen, then, seems to have two quite distinct effects. By contrast, progesterone only seems to inhibit the effect of SSRIs on 5-HT clearance. There appears to be some difference in the mechanism(s) mediating these two effects of estradiol. Evidence was obtained that these effects of estradiol are mediated via activation of membrane as well as nuclear estrogen receptors (ER), indicating a genomic as well as a non-genomic component to these effects. By contrast, the effect of progesterone seems to be mediated primarily by nuclear receptors. A principal goal of this proposal is to extend these studies using other measures, either neurochemical (in vivo microdialysis) or behavioral (forced swimming test (FST)), to see if additional types of evidence can be obtained showing that treatment with female sex hormones either influences SERT function and/or interferes with the ability of SSRIs to inhibit the SERT. In addition, to examine possible mechanisms underlying hormonal effects, experiments are planned to study the plasma membrane distribution of the SERT using biotinylation studies; to examine the role of specific ER subtypes; and to study possible involvement of brain-derived neurotrophic factor (BDNF), as we found its administration to mimic the effect of EB and P on the ability of SSRIs to inhibit the SERT. Although the primary focus is the hormone/SSRI interaction, some studies focus on the inhibitory effect of estrogen alone. Finally, in a rat model of hormone-induced pseudopregnancy and subsequent hormone withdrawal, we will study the effects of high hormone levels administered chronically and their withdrawal in the FST and on the phosphorylated state of TrkB as well as their influence on SSRI/SERT interactions. PUBLIC HEALTH RELEVANCE: By 2020, the World Health Organization has predicted that MDD will be the second leading cause of disease burden worldwide, with women in their reproductive years representing over two-thirds of that estimate since women are twice as likely to suffer from MDD as men. Our studies involve the interaction between ovarian steroids, the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, and the serotonin transporter (SERT), in particular examining the mechanisms by which such steroids interfere with the ability of SSRIs to block the SERT. The results obtained could have important implications for understanding treatment non-response in some women.

描述（由申请人提供）：某些女性患有重度抑郁症（MDD）的脆弱性在女性中的频率比男性更频繁，与荷尔蒙波动有关（每月，怀孕，产后和更年期）。我们最近使用体内计时仪法的技术表明，急性施用卵巢激素（雌二醇苯甲酸酯（EB）或孕激素（P））会影响选择性5-羟色胺再摄取抑制剂（SSRIS）的能力，以改变其最初被认为是其最初的脑细胞靶标的（Serotron）的功能 - 塞罗特蛋白（Seroton）的功能 - 另外，EB而非P，当急性地封闭SERT功能时，通过降低外源施加的5-羟色胺的清除率证明了SERT功能。因此，EB有两个动作。它本身就减慢了5-HT的间隙，这种效果类似于SSRIS引起的效果。人们可能会推测雌激素是基于这种作用的抗抑郁药。但是，我们还发现雌激素会干扰SSRIS降低5-HT间隙的能力。这种影响可能会损害SSRI的抗抑郁作用。因此，雌激素似乎具有两个完全不同的作用。相比之下，孕酮似乎仅抑制SSRI对5-HT清除的影响。 介导雌二醇的两种作用的机制似乎有所不同。有证据表明，雌二醇的这些作用是通过膜的激活以及核雌激素受体（ER）介导的，表明这些作用的基因组和非基因组成分。相比之下，孕酮的作用似乎主要是由核受体介导的。该提案的主要目标是使用其他措施进行这些研究，包括神经化学（体内微透析）或行为（强制游泳测试（FST）），以查看是否可以获得其他类型的证据，表明该治疗女性性激素是否会影响Sert功能和/或对SSRIS的能力进行ssris的能力。此外，为了检查激素作用的可能机制，计划使用生物素化研究研究SERT的质膜分布。检查特定ER亚型的作用；并研究可能参与脑衍生的神经营养因子（BDNF），因为我们发现它的施用模仿了EB和P对SSRIS抑制SERT的能力的影响。尽管主要重点是激素/SSRI相互作用，但一些研究集中于单独的雌激素的抑制作用。最后，在激素诱导的假性孕率和随后的激素戒断的大鼠模型中，我们将研究高激素水平长期施用的高激素水平及其在FST和TRKB磷酸化状态的戒断以及它们对SSRI/SERT相互作用的影响。 公共卫生相关性：到2020年，世界卫生组织已经预测，MDD将成为全球疾病负担的第二大主要原因，而妇女的生殖年份代表了该估计值的三分之二以上，因为女性的MDD可能是男性的两倍。我们的研究涉及卵巢类固醇，选择性5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药的相互作用，以及羟色胺转运蛋白（SERT），特别是检查了这种类固醇干扰SSRIS阻止SERT的能力的机制。获得的结果可能对理解某些女性的治疗无反应具有重要意义。