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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter
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Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter

机译：转基因消除高亲和力抗抑郁药和可卡因敏感性的突触前5-羟色胺转运蛋白。

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摘要

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepres-sants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylene-dioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors flu-oxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autore-ceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.
机译：尽管许多患者未表现出反应或出现令人不愉快的副作用，但以5-羟色胺[即5-羟基色胺（5-HT）]为靶点的抗抑郁药已广泛用于治疗情绪障碍。精神兴奋剂，例如可卡因和3,4-亚甲基-二氧基甲基苯丙胺（即“摇头丸”），也会影响5-HT信号传导。为了帮助剖析5-HT信号对这些试剂和其他试剂的作用，我们开发了转基因小鼠，其中消除了对多种抗抑郁药和可卡因的高亲和力识别。我们的动物拥有5-HT转运蛋白（即SERT，slc6a4）的修饰副本，该蛋白在5-HT结合位点附近带有一个氨基酸取代基I172M。尽管M172取代不影响5-HT的识别，但此突变破坏了转染细胞中许多竞争性拮抗剂的高亲和力结合。在这里，我们证明，在M172敲入小鼠中，基础SERT蛋白水平，5-HT转运速率和5-HT水平正常。但是，SERT M172小鼠对选择性5-HT再摄取抑制剂flu-oxetine和citalopram以及对可卡因的敏感性大大降低。通过一系列的生化，电生理和行为分析，我们证明了该模型的独特性质，并直接建立了SERT是唯一的蛋白质，负责在5-HT1A中5-HT再摄取抑制剂介导的5-HT清除率的改变。受体对突触神经元放电的自动调节，以及用于预测抗抑郁药效用的行为。

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    Brent J. Thompson; Tammy Jessen; L. K. Henry; Julie R. Field; Karen L. Gamble; Paul J. Gresch; Ana M. Carneiro; Rebecca E. Horton; Peter J. Chisnell; Yekaterina Belova; Douglas G. McMahon; Lynette C. Daws; Randy D. Blakely;

  • 作者单位

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, Grand Forks, ND 58203;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Departments of Biological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Psychiatry and Behavioral Sciences, University of Alabama at Birmingham, Birmingham, AL 35233;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Physiology, University of Texas Health Sciences Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232 Departments of Cellular and Structural Biology and Pharmacology, University of Texas Health Sciences Center, San Antonio, TX 78229;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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