5-HT transporter function: Interaction of hormones and antidepressants

5-HT 转运蛋白功能：激素和抗抑郁药的相互作用

• 批准号: 8397527
• 负责人: ALAN FRAZER
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397527
• 关键词: Acute; Afghanistan; Agonist; Antidepressive Agents; Basic Science; Behavior; Behavioral; Biotinylation; Birds; Brain; Brain-Derived Neurotrophic Factor; Caring; Cell membrane; Chronic; Citalopram; Development; Estradiol; Estradiol Benzoate; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exposure to; Female; Fluvoxamine; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Healthcare; Heterozygote; Hippocampus (Brain); Hormonal; Hormones; Impaired cognition; Iraq; K 252a; Knockout Mice; Long-Term Effects; Longitudinal Studies; Major Depressive Disorder; Measures; Mediating; Membrane; Mental Health; Mental disorders; Metabolic Clearance Rate; Microdialysis; Military Personnel; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear Receptors; Ovarian; Ovarian hormone; Patients; Pharmaceutical Preparations; Physiological; Post-Traumatic Stress Disorders; Postpartum Depression; Progesterone; Provider; Rattus; Reporting; Research; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serum; Signaling Molecule; Statutes and Laws; Steroids; Surface; Swimming; Symptoms; System; Techniques; Testing; Time; Training; Veterans; War; Woman; Women' s Health; Women' s Role; base; behavior measurement; cellular targeting; combat; experience; extracellular; improved; in vivo; male; neurochemistry; osmotic minipump; pre-clinical research; prevent; public health relevance; receptor; research study; serotonin transporter; sexual trauma; single episode major depressive disorder

DESCRIPTION (provided by applicant): The vulnerability of some women to develop major depressive disorder (MDD) is associated with hormonal fluctuations. It is likely that effects of gonadal hormones contribute to the development of MDD (as well as postpartum depression) and this may be part of the reason why MDD is more common in females than in males. In spite of this, preclinical research examining the effects of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs)- the drug class of choice for the treatment of MDD- on either behavioral or neurochemical parameters, have mainly used male subjects. In our experiments, effects of SSRIs in female rats were examined. It was found, using the technique of in vivo chronoamperometry, that acute administration of ovarian hormones (estradiol benzoate (EB) or progesterone (P)), either given systemically or locally into the CA3 region of the hippocampus, interferes with the ability of SSRIs to inhibit the function of what is widely considered their initial cellular target in brain- the serotonin transporter (SERT). In addition, EB but not P blocked the function of the SERT. Further, there appears to be some difference in the mechanism(s) mediating these two effects of estradiol. Further, these two effects of EB would be expected to exert counteracting effects on the ability of estradiol, or estradiol plus progesterone, to improve the efficacy of SSRIs when given in combination with such treatment. Evidence was obtained that these effects of estradiol are mediated via activation of membrane as well as nuclear estrogen receptors (ER). By contrast, the effect of progesterone seems to be mediated primarily by nuclear receptors. These previous results provide the rationale for the studies in the current proposal, whose principal goal is to extend these studies using neurochemical or behavioral measures to see if further evidence can be obtained that treatment with female sex hormones either influences SERT function and/or interferes with the ability of SSRIs to inhibit the SERT. Experiments will be carried out in ovariectomized female rats. The new techniques to be used are in vivo microdialysis and the forced swimming test (FST). Our hypotheses are that acute treatment with either estradiol or progesterone will block the ability of locally applied fluvoxamine, an SSRI, either to elevate extracellular levels of serotonin in the hippocampus or its ability to decrease immobility or increase swimming behavior in the FST. In addition, to examine possible mechanisms underlying the hormonal effects: (1) biotinylation studies on synaptosomal membranes will be carried out to examine the plasma membrane distribution of the SERT after hormone treatment; (2) using chronoamperometry, two approaches will be used, namely the use of specific estrogen receptor (ER1 or ER2) knockout mice and the effects of selective estrogen receptor agonists in rats, to study the role of these estrogen receptor subtypes in mediating the effects of estrogen; and again using chronoamperometry (3) the possible involvement of brain-derived neurotrophic factor (BDNF) as an intermediary in the effect of estradiol on the action of an SSRI will be examined by using an antagonist of the receptor for BDNF. Finally, we will investigate if longer-term, more clinically appropriate treatment with E2 alone or E2+P alters SERT function and/or effects produced by an SSRI given chronically.

描述（由申请人提供）： 某些妇女患主要抑郁症（MDD）的脆弱性与荷尔蒙波动有关。性腺激素的影响可能有助于MDD的发展（以及产后抑郁症），这可能是MDD在女性中比男性更常见的原因。尽管如此，临床前研究研究了抗抑郁药的作用，尤其是选择性5-羟色胺再摄取抑制剂（SSRIS） - 治疗MDD-对行为或神经化学参数的治疗的药物类别主要使用了男性受试者。在我们的实验中，检查了SSRI对雌性大鼠的影响。使用体内计时仪法的技术，急性施用卵巢激素（雌二醇苯甲酸酯（EB）或孕激素（P）），实际上或在全身或局部给予海马的CA3区域，与SSRIS的能力相互促进了最初的小细胞的功能，这些疗效是促进了最初的小细胞的功能。另外，EB但不阻止SERT的功能。此外，介导雌二醇的这两种作用的机制似乎有所不同。此外，EB的这两种影响预计将对雌二醇或雌二醇加孕酮的能力产生抵消作用，以提高SSRIS与这种治疗的功效。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。相比之下，孕酮的作用似乎主要是由核受体介导的。这些先前的结果为当前提案中的研究提供了理由，其主要目标是使用神经化学或行为措施扩展这些研究，以查看是否可以获得进一步的证据，即是否可以获得对女性性激素治疗的治疗，会影响SERT功能和/或干扰SSRIS抑制SERT的能力。实验将在卵巢切除的雌性大鼠中进行。要使用的新技术是体内微透析和强制游泳测试（FST）。我们的假设是，用雌二醇或孕激素急性治疗将阻止局部施用的氟氟众胺（SSRI）的能力，即SSRI，可以提高海马中羟色胺的细胞外羟色胺水平，或者其降低FST中固定性或增加游泳行为的能力。此外，为了检查激素作用的可能机制：（1）将进行突触体膜的生物素化研究，以检查激素处理后SERT的质膜分布； （2）使用计时度测定法，将使用两种方法，即使用特定的雌激素受体（ER1或ER2）基因敲除小鼠以及选择性雌激素受体激动剂在大鼠中的影响，以研究这些雌激素受体亚型在介导雌激素作用中的作用；并再次使用年级体体测量法（3）将通过使用BDNF的受体的拮抗剂来检查脑衍生的神经营养因子（BDNF）作为雌二醇对SSRI作用的中介的参与。最后，我们将研究是否单独使用E2，更临床上适当的治疗，或者E2+P可以改变SSRI产生的SERT功能和/或效应。