5-HT transporter function: Interaction of antidepressants and hormones

描述（由申请人提供）：一些女性易患重度抑郁症（MDD），这种疾病在女性中比在男性中更常见，与激素波动（月经、怀孕、产后和更年期）有关。我们最近使用体内时间电流测定技术表明，卵巢激素（雌二醇苯甲酸酯（EB）或孕酮(P)）的急性给药会影响选择性血清素再摄取抑制剂（SSRIs）的能力，从而改变被广泛认为是它们在大脑中的初始细胞靶点-血清素转运体（SERT）的功能。此外，急性给予EB而非P，可阻断SERT功能，外源性血清素清除率降低。因此，EB有两个动作。就其本身而言，它减缓了5-羟色胺的清除，其效果与SSRIs类似。有人可能会根据这种作用推测雌激素是抗抑郁药。然而，我们也发现雌激素会干扰SSRIs减缓5-HT清除的能力。这种效应可能会削弱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，黄体酮似乎只抑制SSRIs对5-HT清除的作用。雌二醇介导这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激活膜和核雌激素受体（ER）介导的，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由核受体介导。本提案的主要目标是使用其他方法(神经化学（体内微透析）或行为（强迫游泳试验（FST））来扩展这些研究，看看是否可以获得其他类型的证据，表明用女性性激素治疗会影响SERT功能和/或干扰SSRIs抑制SERT的能力。此外，为了研究激素作用的可能机制，计划利用生物素化研究来研究SERT的质膜分布；研究特定ER亚型的作用；并研究脑源性神经营养因子（BDNF）的可能参与，因为我们发现其管理模拟EB和P对SSRIs抑制SERT能力的影响。虽然主要关注激素/SSRI的相互作用，但也有一些研究关注单独雌激素的抑制作用。最后，在激素诱导的假妊娠和随后的激素戒断的大鼠模型中，我们将研究长期高水平的激素对FST和TrkB磷酸化状态的影响，以及它们对SSRI/SERT相互作用的影响。

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.