Long-Term Duloxetine Treatment Normalizes Altered Brain-Derived Neurotrophic Factor Expression in Serotonin Transporter Knockout Rats through the Modulation of Specific Neurotrophin Isoforms
Long-Term Duloxetine Treatment Normalizes Altered Brain-Derived Neurotrophic Factor Expression in Serotonin Transporter Knockout Rats through the Modulation of Specific Neurotrophin Isoforms
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DOI：
10.1124/mol.109.063081
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发表时间：
2010-05-01
影响因子：
3.6
通讯作者：
Riva, Marco A.
中科院分区：
文献类型：
--
作者：
Calabrese, Francesca;Molteni, Raffaella;Riva, Marco A.
多巴胺能系统的功能障碍涉及许多精神疾病的病因，包括重度抑郁症。情绪障碍的主要易感基因也与多巴胺能系统有关：其中一个基因编码5-羟色胺转运蛋白（SERT），这是抗抑郁药物作用的主要靶点。我们最近已经证明，SERT基因敲除（KO）大鼠，产生的N-乙基-N-亚硝基脲诱导的诱变，显示减少表达的神经营养蛋白脑源性神经营养因子（BDNF）在海马和前额叶皮层，这表明抑郁症的脆弱性可以与受损的神经元可塑性。在本研究中，我们证明，慢性治疗与抗抑郁药度洛沙汀（DLX）是能够正常化的BDNF mRNA编码外显子（IX）的表达在海马和前额叶皮层的SERT KO大鼠通过调制选定的神经营养因子转录，其表达上调DLX只在SERT KO大鼠。另一方面，DLX对突变大鼠额叶皮质BDNF蛋白的调节作用被取消。这些数据表明，具有5-羟色胺转运蛋白遗传缺陷的动物保持了对抗抑郁药物反应的神经可塑性变化的能力。由于这些动物表现出抑郁样行为，BDNF水平的区域和亚型特异性增加可能是长期抗抑郁治疗激活的机制，以恢复在5-羟色胺转运蛋白遗传功能障碍下存在缺陷的正常可塑性。
Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.