Repeated swim impairs serotonin clearance via a corticosterone-sensitive mechanism: organic cation transporter 3, the smoking gun.
Repeated swim impairs serotonin clearance via a corticosterone-sensitive mechanism: organic cation transporter 3, the smoking gun.
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DOI：
10.1523/jneurosci.2740-10.2010
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发表时间：
2010-11-10
期刊：
影响因子：
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通讯作者：
Daws LC
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文献类型：
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作者：
Baganz N;Horton R;Martin K;Holmes A;Daws LC
下丘脑-垂体-肾上腺(HPA)轴的激活与边缘脑区细胞外5-羟色胺(5-HT)的增加有关。这种情况发生的机制尚不清楚。一种途径可能是通过HPA轴依赖的5-羟色胺转运体(SERT)功能受损，这是5-羟色胺的高亲和力摄取机制。与这一想法一致的是，我们发现，反复游泳的小鼠海马区5-羟色胺清除率显著降低，这是一种已知的激活HPA轴的刺激。然而，这种现象也发生在缺乏SERT的小鼠身上，排除了SERT作为一种机制。有机阳离子转运蛋白3(Oct3)是脑内5-羟色胺的重要调节因子。此外，在HPA轴激活时释放的皮质酮在10月3日之前阻止5-羟色胺的摄取。反复游泳导致血浆皮质酮持续升高，与皮质酮长期阻断一致，我们发现这些小鼠Oct3的表达和功能都降低了。重要的是，重复游泳以降低5-羟色胺清除率的这种效果是皮质酮依赖的，这在肾上腺切除的小鼠中没有证明，在肾上腺切除的小鼠中，血浆皮质酮水平基本上检测不到。行为学上，反复游泳的小鼠在尾部悬挂试验中不动的时间比对照组小，但对SERT和去甲肾上腺素转运体选择性抗抑郁药的反应相似。总之，这些结果表明，HPA轴激活后5-羟色胺清除减少可能至少部分是由皮质酮敏感的Oct3介导的，开发的选择性靶向Oct3的药物(与皮质酮不同)可能是开发新型抗抑郁药物的候选药物。
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with increased extracellular serotonin (5-HT) in limbic brain regions. The mechanism through which this occurs remains unclear. One way could be via HPA axis-dependent impairment of serotonin transporter (SERT) function, the high-affinity uptake mechanism for 5-HT. Consistent with this idea, we found that 5-HT clearance rate in hippocampus was dramatically reduced in mice exposed to repeated swim, a stimulus known to activate the HPA axis. However, this phenomenon also occurred in mice lacking SERT, ruling out SERT as a mechanism. The organic cation transporter 3 (OCT3) is emerging as an important regulator of brain 5-HT. Moreover, corticosterone, which is released upon HPA axis activation, blocks 5-HT uptake by OCT3. Repeated swim produced a persistent elevation in plasma corticosterone, and consistent with prolonged blockade by corticosterone, we found that OCT3 expression and function was reduced in these mice. Importantly, this effect of repeated swim to reduce 5-HT clearance rate was corticosterone-dependent, as evidenced by its absence in adrenalectomized mice, in which plasma corticosterone levels were essentially undetectable. Behaviorally, mice subjected to repeated swim spent less time immobile in the tail suspension test than control mice, but responded similarly to SERT and norepinephrine transporter selective antidepressants. Together, these results show that reduced 5-HT clearance following HPA axis activation is likely mediated, at least in part, by the corticosterone-sensitive OCT3, and that drugs developed to selectively target OCT3 (unlike corticosterone) may be candidates for the development of novel antidepressant medications.