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: 8246298
• 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/8246298
• 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; 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. PUBLIC HEALTH RELEVANCE: With the recent combat deployments in Iraq and Afghanistan, treating the mental health care needs of veterans will be a continuing challenge for years to come. An estimated 25 to 30% of veterans of the wars in Iraq and Afghanistan have reported symptoms of a mental disorder or cognitive dysfunction (Seal et al. 2007). Female veterans were twice as likely as their male counterparts to have experienced a major depressive episode in the last year. Further evidence of the increasing role of women in the military is exemplified by Senator Patty Murray introducing the Women Veterans Health Care Improvement Act of 2008 (S. 2799). Requirements of the legislation would include a long-term study on the health of women veterans who served on active duty in Iraq, an assessment of barriers to health care for women in the VA system, and training for providers on the care of women who have suffered sexual trauma and those with PTSD. Our basic research studies could have treatment implications for patients with either MDD and/or PTSD.

描述（由申请人提供）： 一些女性容易患重度抑郁症（MDD）与荷尔蒙波动有关。性腺激素的影响可能会导致重度抑郁症（以及产后抑郁症）的发生，这可能是重度抑郁症在女性中比男性更常见的部分原因。尽管如此，检验抗抑郁药，特别是选择性血清素再摄取抑制剂（SSRI）（治疗重度抑郁症的首选药物类别）对行为或神经化学参数影响的临床前研究主要使用男性受试者。在我们的实验中，研究了 SSRIs 对雌性大鼠的影响。使用体内计时电流分析技术发现，急性施用卵巢激素（苯甲酸雌二醇 (EB) 或黄体酮 (P)），无论是全身还是局部给予海马 CA3 区域，都会干扰 SSRI 的能力抑制被广泛认为是其在大脑中最初的细胞目标——血清素转运蛋白（SERT）的功能。此外，EB而非P阻断了SERT的功能。此外，介导雌二醇这两种作用的机制似乎存在一些差异。此外，当与此类治疗联合使用时，EB的这两种作用预计会对雌二醇或雌二醇加黄体酮提高SSRIs功效的能力产生抵消作用。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）的激活介导的。相比之下，黄体酮的作用似乎主要由核受体介导。这些先前的结果为当前提案中的研究提供了基本原理，其主要目标是使用神经化学或行为测量来扩展这些研究，看看是否可以获得进一步的证据，证明女性性激素治疗会影响 SERT 功能和/或干扰SSRIs 抑制 SERT 的能力。实验将在切除卵巢的雌性大鼠中进行。将使用的新技术是体内微透析和强迫游泳测试（FST）。我们的假设是，用雌二醇或黄体酮进行急性治疗将阻止局部应用氟伏沙明（一种 SSRI）的能力，无论是提高海马细胞外血清素水平，还是减少 FST 中不动或增加游泳行为的能力。此外，为了检查激素影响的可能机制：（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)采用计时安培法，将采用两种方法，即使用特异性雌激素受体(ER1或ER2)基因敲除小鼠和选择性雌激素受体激动剂对大鼠的作用，来研究这些雌激素受体亚型在介导作用中的作用雌激素；并再次使用计时电流分析法(3)，通过使用BDNF受体拮抗剂来检查脑源性神经营养因子(BDNF)作为雌二醇对SSRI作用的影响的中介的可能参与。最后，我们将研究单独使用 E2 或 E2+P 进行更长期、更临床合适的治疗是否会改变长期服用 SSRI 所产生的 SERT 功能和/或效果。 公共卫生相关性： 随着最近在伊拉克和阿富汗的战斗部署，满足退伍军人的心理健康护理需求将成为未来几年的持续挑战。据估计，25% 至 30% 的伊拉克和阿富汗战争退伍军人报告有精神障碍或认知功能障碍的症状（Seal 等人，2007 年）。去年，女性退伍军人经历严重抑郁症的可能性是男性退伍军人的两倍。参议员帕蒂·默里 (Patty Murray) 提出的 2008 年《女退伍军人医疗保健改善法案》(S. 2799) 进一步证明了女性在军队中的作用日益增强。该立法的要求将包括对在伊拉克服役的女退伍军人的健康状况进行长期研究，对退伍军人事务部系统中女性医疗保健的障碍进行评估，以及对服务提供者进行关于照顾那些在伊拉克服役的女性退伍军人的培训。遭受过性创伤和患有创伤后应激障碍（PTSD）的人。我们的基础研究可能对患有抑郁症和/或创伤后应激障碍的患者产生治疗影响。