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）：在出生后不久的特定时期内，用5-羟色胺再摄取抑制抗抑郁药（SRI）治疗小鼠或大鼠，导致成年后焦虑和抑郁样行为增加。在这里，我们将扩大我们的研究使用伏安法的方法来调查的作用，5-羟色胺转运蛋白（SERT）在焦虑和抑郁症，包括这个重要的模型，出生后抑制5-羟色胺再摄取。我们将使用计时电流法来测定出生后SRI治疗引起的青春期和成年期血清素摄取率的变化。我们以前已经证明，使用高速计时电流法来测量脑突触体中5-羟色胺的摄取是上级传统的放射化学方法。我们还将利用定量放射自显影来评估5-羟色胺转运蛋白结合位点的变化，以确定SERT功能和表达的改变是否相关。最近有证据表明，海马SERT功能和表达增加，在早期和中期的成年期在正常动物。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开始。我们还将确定它是否存在于海马体以外的脑区，这些脑区由神经元能系统支配，对调节焦虑和情绪很重要。此外，我们将测试的假设，出生后管理的SRIs破坏正常的青春期和成人的SERT功能和表达的发展。这项研究的结果将使我们能够解释是否在正常SERT的发展发生在青少年和/或成人的时间范围内的变化是关键因素，导致出生后SRI暴露引起的表型改变。这对我们理解多巴胺能系统的正常发育和与早期生活暴露于SRI相关的改变轨迹有影响。公共卫生关系：小鼠或大鼠在出生后短时间内使用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的增加。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，血清素再摄取的减少是否会持续很长时间。我们将探讨早期接触抗抑郁药改变血清素转运体功能和表达的正常发育的想法。这项研究的结果将增加我们对正常大脑发育和与早期接触抗抑郁药有关的发育轨迹改变的理解。