Postnatal Antidepressant Effects on Periadolescent SERT Function by Voltammetry

描述(由申请人提供)：在出生后不久的特定时期使用5-羟色胺再摄取抑制抗抑郁药(SRI)治疗小鼠或大鼠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5-羟色胺转运体(SERT)在焦虑和抑郁中的作用，以包括这一出生后抑制5-羟色胺再摄取的重要模型。我们将使用计时电流法来确定青春期前和成年后SRI治疗引起的5-羟色胺摄取率的变化。我们以前已经证明，使用高速计时电流法测量脑突触体内的5-羟色胺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来评估5-羟色胺转运体结合位点的变化，以确定SERT功能和表达的变化是否相关。最近的证据表明，在正常动物的早期和中期，海马区SERT的功能和表达增加。这项研究的设计将使我们能够调查这种发育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，这些区域由5-羟色胺能系统支配，对调节焦虑和情绪很重要。此外，我们还将检验这样一种假设，即出生后服用SRIs会干扰青春期和成人期间SERT功能和表达的正常发育。这项研究的结果将使我们能够解释发生在青春期和/或成年期的正常SERT发育的变化是否是导致出生后SRI暴露引起的表型变化的关键因素。这对我们理解5-羟色胺能系统的正常发育以及与早期接触SRI有关的改变轨迹具有重要意义。公共卫生相关性：小鼠或大鼠出生后短期使用5-羟色胺再摄取抑制抗抑郁药物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停止药物治疗后5-羟色胺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物会改变5-羟色胺转运体功能和表达的正常发育。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物相关的改变发育轨迹的理解。

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.