Postnatal Antidepressant Effects on Periadolescent SERT Function by Voltammetry

伏安法研究产后抗抑郁对青春期 SERT 功能的影响

• 批准号: 7796765
• 负责人: ANNE MILASINCIC ANDREWS
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796765
• 关键词: Adolescence; Adolescent; Adult; Affinity; Animals; Antidepressive Agents; Anxiety; Arts; Attenuated; Behavior; Binding; Binding Sites; Birth; Brain; Brain Stem; Brain region; Carrier Proteins; Development; Elements; Exposure to; Hippocampus (Brain); Life; Measures; Mental Depression; Methods; Modeling; Moods; Mus; Paroxetine; Pharmaceutical Preparations; Phenotype; Principal Investigator; Quantitative Autoradiography; Rattus; Research Design; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Speed; Synaptosomes; System; TNFRSF5 gene; Testing; Time; depressive symptoms; early life exposure; emerging adult; postnatal; programs; public health relevance; radiochemical; reuptake; serotonin transporter; tyrosine kinase ABL1; uptake

DESCRIPTION (provided by applicant): Treatment of mice or rats with serotonin reuptake inhibiting antidepressants (SRIs) during a specific period shortly after birth results in increased anxiety- and depressive-like behavior in adulthood. Here, we will extend our studies on the use of voltammetry methods to investigate the role of the serotonin transporter (SERT) in anxiety and depression to include this important model of postnatal inhibition of serotonin reuptake. We will use chronoamperometry to determine changes in serotonin uptake rates during periadolescence and adulthood arising from postnatal treatment with an SRI. We have demonstrated previously that the use of high-speed chronoamperometry to measure serotonin uptake in brain synaptosomes is superior to traditional radiochemical methods. We will also utilize quantitative autoradiography to evaluate changes in serotonin transporter binding sites to determine whether alterations in SERT function and expression are correlated. There is recent evidence that hippocampal SERT function and expression increase during early and middle adult periods in normal animals. The design of this study will allow us to investigate whether this developmental trajectory begins prior to adulthood. We will also determine whether it is present in brain regions other than hippocampus that are innervated by the serotonergic system and are important for modulating anxiety and mood. Moreover, we will test the hypothesis that postnatal administration of SRIs disrupts normal periadolescent and adult development of SERT function and expression. The results of this study will allow us to interpret whether alterations in normal SERT development occurring during adolescent and/or adult time frames are key elements contributing to the altered phenotype induced by postnatal SRI exposure. This has ramifications for our understanding of normal development of the serotonergic system and for altered trajectories related to early life exposure to SRIs. PUBLIC HEALTH RELEVANCE: Treatment of mice or rats with serotonin reuptake inhibiting antidepressants for a short period after birth leads to elevated anxiety and depressive behavior in adulthood. We will use a state-of-the-art electrochemical method to determine whether reductions in serotonin reuptake persist long after the cessation of drug treatment. We will explore the idea that early life exposure to antidepressants alters the normal development of serotonin transporter function and expression. The results of this study will increase our understanding of normal brain development and altered developmental trajectories related to early life exposure to antidepressants.

描述（由申请人提供）：在小鼠或大鼠出生后不久的特定时期用抑制血清素再摄取的抗抑郁药（SRI）进行治疗会导致成年后焦虑和抑郁样行为的增加。在这里，我们将扩展我们的研究，使用伏安法来研究血清素转运蛋白（SERT）在焦虑和抑郁中的作用，以包括这种出生后抑制血清素再摄取的重要模型。我们将使用计时安培法来确定青春期和成年期因产后 SRI 治疗而引起的血清素摄取率的变化。我们之前已经证明，使用高速计时电流法测量大脑突触体中血清素的摄取优于传统的放射化学方法。我们还将利用定量放射自显影术来评估血清素转运蛋白结合位点的变化，以确定 SERT 功能和表达的变化是否相关。最近有证据表明，正常动物的海马 SERT 功能和表达在成年早期和中期会增加。这项研究的设计将使我们能够调查这种发展轨迹是否在成年之前就开始了。我们还将确定它是否存在于海马体以外的大脑区域中，这些区域受血清素能系统支配，并且对于调节焦虑和情绪很重要。此外，我们将检验以下假设：出生后服用 SRI 会破坏 SERT 功能和表达的正常青春期和成人发育。这项研究的结果将使我们能够解释青少年和/或成人时期发生的正常 SERT 发育的改变是否是导致出生后 SRI 暴露引起的表型改变的关键因素。这对于我们理解血清素能系统的正常发育以及与生命早期接触 SRI 相关的变化轨迹具有影响。公共卫生相关性：小鼠或大鼠在出生后短时间内接受抑制血清素再摄取的抗抑郁药治疗会导致成年后焦虑和抑郁行为加剧。我们将使用最先进的电化学方法来确定在药物治疗停止后很长一段时间内血清素再摄取的减少是否持续存在。我们将探讨生命早期接触抗抑郁药物会改变血清素转运蛋白功能和表达的正常发育的观点。这项研究的结果将增加我们对正常大脑发育以及与早期接触抗抑郁药物相关的发育轨迹改变的理解。