The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice
The effects of chronic norepinephrine transporter inactivation on seizure susceptibility in mice
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DOI：
10.1038/sj.npp.1300847
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发表时间：
2006-04-01
影响因子：
7.6
通讯作者：
Weinshenker, D
中科院分区：
文献类型：
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作者：
Ahern, TH;Javors, MA;Weinshenker, D
癫痫和抑郁症是共病性疾病，但其相关机制尚未确定。传统上，许多抗抑郁药被认为会增加癫痫发作的发生率，尽管这仍然存在争议，而且目前还不清楚哪些药物应该用于治疗癫痫和抑郁症患者。由于神经递质去甲肾上腺素（NE）具有抗抑郁和抗惊厥的特性，我们推测NE转运蛋白（NET）抑制剂抗抑郁药可能是共病个体的治疗候选药物。为了验证这一观点，我们评估了选择性NET抑制剂瑞博西汀长期给药（通过渗透微泵）对小鼠氟乙烯诱导癫痫发作的影响。我们发现，reboxesterone既有促惊厥和抗惊厥的特性，它降低了癫痫发作阈值和最大癫痫发作的严重程度。NET基因敲除（NET KO）小鼠基本上表现出对氟乙烯诱导的癫痫发作的影响，并且这种趋势扩展到戊四唑和最大电休克癫痫发作（MES）。此外，在NET KO小鼠中，reboxalone没有进一步的作用，证明了reboxalone对NET的特异性。接下来，我们测试了其他类型的抗抑郁药（地昔帕明、丙咪嗪、舍曲林、安非他酮和文拉法辛）对癫痫易感性的慢性和急性作用。只有文拉法辛没有促惊厥活性，并保留了一些抗惊厥活性。这些结果表明，慢性抗抑郁药物治疗具有促惊厥和抗惊厥作用，文拉法辛是治疗癫痫和抑郁症合并症的良好候选药物。
Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine ( NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter ( NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration ( via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout ( NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures ( MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants ( desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.