Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice
Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice
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DOI：
10.1073/pnas.0800466105
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发表时间：
2008-12-02
影响因子：
11.1
通讯作者：
Daws, Lynette C.
中科院分区：
文献类型：
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作者：
Baganz, Nicole L.;Horton, Rebecca E.;Daws, Lynette C.
情绪障碍造成许多痛苦，是全球生产力损失的最大原因。虽然多种药物，沿着行为疗法，已被证明对某些人有效，但数百万人缺乏有效的治疗选择。一种常见的5-羟色胺（5-HT）转运蛋白（5-HTT/SERT，SLC 6A 4）多态性被认为在体内赋予较低的5-HTT表达，并增加多种情绪障碍的风险，包括焦虑，酗酒和重度抑郁症。重要的是，这种变体还与对选择性5-HT再吸收抑制剂抗抑郁药的反应性降低有关。我们假设，在5-HTT表达组成性减少的个体中，抗抑郁反应的降低可能是由于大脑中抑制5-HT的其他基因的代偿性表达而引起的。功能上调的5-HT替代转运蛋白可能会阻止细胞外5-HT升高到足以触发治疗益处所需的适应性神经化学事件的水平。在这里，我们证明了有机阳离子转运蛋白3型（OCT 3，SLC 22 A3），这也运输5-HT，表达上调与组成性减少5-HTT表达的小鼠的大脑。此外，OCT阻断剂decyphin-22减少了5-HT清除率，并在这些小鼠中发挥抗抑郁样作用，但在WT动物中没有。当5-HTT表达或功能受损时，OCT 3可能是介导β-羟色胺能信号传导的重要转运蛋白。
Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressant-like effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised.