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: 7642948
• 负责人: ANNE MILASINCIC ANDREWS
• 金额: $ 7.19万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642948
• 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; 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; depression; depressive symptoms; 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）：在特定时期内用5-羟色胺再摄取的小鼠或大鼠在出生后不久的特定时期，导致成年期的焦虑和抑郁样行为增加。在这里，我们将扩展有关使用伏安法方法来研究5-羟色胺转运蛋白（SERT）在焦虑和抑郁中的作用的研究，以包括这种重要的血清素再摄取后血清素抑制作用的模型。我们将使用年级体体测量法来确定周围杂质和成年期在SRI产后治疗引起的5-羟色胺摄取率的变化。我们以前已经证明，使用高速年级体体测量测量脑突触体中的5-羟色胺摄取量优于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功能和表达的变化是否相关。最近有证据表明，正常动物的早期和中期成年时期海马SERT功能和表达增加。这项研究的设计将使我们能够研究这种发展轨迹是否在成年前开始。我们还将确定它是否存在于脑部能系统神经影响的海马以外的大脑区域中，对于调节焦虑和情绪很重要。此外，我们将检验以下假设：SRI后产后给药会破坏正常的周围和成人SERT功能和表达的发展。这项研究的结果将使我们能够解释青少年和/或成人时间范围期间正常SERT发育发生的变化是否是导致产后SRI暴露引起的改变表型的关键要素。这对我们了解血清素能系统的正常发展以及与早期生活暴露于SRI的正常发展的影响有很大的影响。公共卫生相关性：用5-羟色胺再摄取的小鼠或大鼠在出生后短时间内抑制抗抑郁药的治疗导致焦虑和成年时的抑郁行为升高。我们将使用一种最先进的电化学方法来确定在停止药物治疗后很长一段时间降低5-羟色胺再摄取的减少。我们将探讨这样一种观念，即早期寿命暴露于抗抑郁药会改变5-羟色胺转运蛋白功能和表达的正常发展。这项研究的结果将增加我们对正常脑发育的理解，并改变了与早期生活暴露于抗抑郁药有关的发育轨迹。