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: 7986197
• 负责人: ALAN FRAZER
• 金额: $ 33.41万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986197
• 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; response; 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）：一些女性易患重度抑郁症（MDD），女性比男性更常见，与激素波动（每月、妊娠、产后和更年期）有关。最近，我们使用体内计时电流法技术表明，卵巢激素（苯甲酸雌二醇（EB）或孕酮（P））的急性给药会影响选择性5-羟色胺再摄取抑制剂（SSRI）改变脑中被广泛认为是其初始细胞靶点-5-羟色胺转运蛋白（SERT）功能的能力。此外，EB而不是P，当急性给药时，阻断SERT功能，表现为外源性5-羟色胺清除率降低。因此，EB有两个动作。就其本身而言，它减缓了5-HT的清除，这种效果类似于SSRIs引起的效果。基于这种作用，人们可能会推测雌激素是抗抑郁的。然而，我们也发现雌激素干扰SSRIs减缓5-HT清除的能力。这种作用可能会损害SSRIs的抗抑郁作用。因此，雌激素似乎有两种截然不同的作用。相比之下，孕酮似乎只抑制SSRIs对5-HT清除的作用。 在调节雌二醇这两种作用的机制上似乎存在一些差异。有证据表明，雌二醇的这些作用是通过激活膜以及核雌激素受体（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由核受体介导。本提案的主要目标是使用其他措施扩展这些研究，无论是神经化学（体内微透析）或行为（强迫游泳试验（FST）），看看是否可以获得其他类型的证据，表明女性性激素治疗影响SERT功能和/或干扰SSRIs抑制SERT的能力。此外，检查可能的机制激素的影响，实验计划研究质膜分布的SERT使用生物素化研究;检查特定的ER亚型的作用;并研究可能参与脑源性神经营养因子（BDNF），因为我们发现它的管理，以模仿EB和P的SSRIs的能力，抑制SERT的效果。虽然主要焦点是激素/SSRI相互作用，但一些研究集中在雌激素单独的抑制作用上。最后，在大鼠模型中的激素诱导的pseudopregulatory和随后的激素戒断，我们将研究长期给予高激素水平和他们的撤退在FST和磷酸化状态的TrkB的影响，以及它们对SSRI/SERT相互作用。 公共卫生相关性：世界卫生组织预测，到2020年，MDD将成为全球疾病负担的第二大原因，育龄妇女占估计数的三分之二以上，因为妇女患MDD的可能性是男性的两倍。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）类抗抑郁药和5-羟色胺转运蛋白（SERT）之间的相互作用，特别是研究此类类固醇干扰SSRI阻断SERT能力的机制。获得的结果可能有重要的意义，了解治疗无反应，在一些妇女。