Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior.
Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior.
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DOI：
10.1523/jneurosci.0360-09.2009
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发表时间：
2009-04-29
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影响因子：
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通讯作者：
Wemmie JA
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文献类型：
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作者：
Coryell MW;Wunsch AM;Haenfler JM;Allen JE;Schnizler M;Ziemann AE;Cook MN;Dunning JP;Price MP;Rainier JD;Liu Z;Light AR;Langbehn DR;Wemmie JA
没有动物模型可以复制人类抑郁症的复杂性。然而，啮齿动物的一些行为测试对抗抑郁药敏感，因此可能会挖掘重要的潜在生物因素。这些模型也可能为发现新的治疗方法提供最好的机会。在这里，我们使用了其中的几个模型来测试酸敏感离子通道-1a（ASIC 1a）可能被靶向减少抑郁症的假设。在强迫游泳试验、悬尾试验和不可预测的轻度压力下，对小鼠的ASIC 1a进行遗传破坏，产生了抗抑郁样作用。在强迫游泳试验中，药理学抑制ASIC 1a也具有抗抑郁样作用。强迫游泳试验中ASIC 1a中断的影响独立于几种常用的抗抑郁药，并与之相加。此外，ASIC 1a中断干扰了抑郁症的一个重要生化标志物，即应激减少海马中BDNF的能力。用病毒载体将ASIC 1a恢复到ASIC 1a −/−小鼠的杏仁核中，逆转了强迫游泳试验的效果，这表明杏仁核是ASIC 1a在抑郁相关行为中发挥作用的关键部位。这些数据与强调杏仁核在情绪调节中的重要性的临床研究一致，并表明ASIC 1a拮抗剂可以有效地对抗抑郁症。
No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments. Here, we used several of these models to test the hypothesis that the acid-sensing ion channel-1a (ASIC1a) might be targeted to reduce depression. Genetically disrupting ASIC1a in mice produced antidepressant-like effects in the forced swim test, the tail suspension test, and following unpredictable mild stress. Pharmacologically inhibiting ASIC1a also had antidepressant-like effects in the forced swim test. The effects of ASIC1a disruption in the forced swim test were independent of and additive to those of several commonly used antidepressants. Furthermore, ASIC1a disruption interfered with an important biochemical marker of depression, the ability of stress to reduce BDNF in the hippocampus. Restoring ASIC1a to the amygdala of ASIC1a−/− mice with a viral vector reversed the forced swim test effects, suggesting that the amygdala is a key site of ASIC1a action in depression-related behavior. These data are consistent with clinical studies emphasizing the importance of the amygdala in mood regulation, and suggest that ASIC1a antagonists may effectively combat depression.