5-HT transporter function: Interaction of antidepressants and hormones

描述(由申请人提供)：一些女性易患严重抑郁障碍(MDD)，女性比男性更常见，这与荷尔蒙波动(每月、怀孕、产后和更年期)有关。最近，我们使用体内计时安培技术表明，急性给予卵巢激素(苯甲酸雌二醇(EB)或孕酮(P))会影响选择性5-羟色胺再摄取抑制剂(SSRIs)改变其在大脑中的初始细胞靶点--5-羟色胺转运体(SERT)--功能的能力。此外，当给予EB而不是P时，SERT功能被阻断，这表现为外源性应用的5-羟色胺清除减少。因此，EB有两个动作。就其本身而言，它会减缓5-羟色胺的清除，这一效果类似于SSRI引起的效果。基于这种作用，人们可能会推测雌激素是一种抗抑郁药物。然而，我们也发现雌激素可以干扰SSRI减慢5-羟色胺清除的能力。这样的效果可能会影响SSRI的抗抑郁作用。因此，雌激素似乎有两种截然不同的影响。相反，黄体酮似乎只抑制SSRIs对5-羟色胺清除的影响。在调节雌二醇的这两种作用的机制上(S)似乎有一些不同。有证据表明，雌二醇的这些作用是通过膜和核雌激素受体(ER)的激活来介导的，这表明这些作用既有基因组成分，也有非基因组成分。相比之下，黄体酮的作用似乎主要是由核受体介导的。这项建议的一个主要目标是使用其他方法扩展这些研究，无论是神经化学方法(体内微透析)还是行为方法(强迫游泳试验(FST))，看看是否可以获得更多类型的证据，表明女性性激素治疗要么影响SERT功能，要么干扰SSRI抑制SERT的能力。此外，为了研究激素效应的可能机制，计划进行实验，利用生物素化研究SERT的质膜分布；检查特定ER亚型的作用；以及研究脑源性神经营养因子(BDNF)的可能参与，因为我们发现它的给药模拟EB和P对SSRI抑制SERT能力的影响。虽然主要关注的是激素/SSRI的相互作用，但也有一些研究只关注雌激素的抑制作用。最后，在激素诱导假孕和随后激素停用的大鼠模型中，我们将研究在FST长期给予和停用高激素水平对TrkB磷酸化状态的影响以及它们对SSRI/SERT相互作用的影响。 与公共卫生相关：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，育龄妇女将占这一估计数的三分之二以上，因为妇女患MDD的可能性是男子的两倍。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)类抗抑郁药物和5-羟色胺转运体(SERT)之间的相互作用，特别是研究了这些类固醇干扰SSRI阻断SERT的能力的机制。所获得的结果可能对了解一些女性的治疗无反应具有重要意义。

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.