Comparative Transcriptomic Analysis of the Effects of Antidepressant Drugs in Stress-Susceptible Mice.
Comparative Transcriptomic Analysis of the Effects of Antidepressant Drugs in Stress-Susceptible Mice.
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DOI：
10.1016/j.biopsych.2016.10.022
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发表时间：
2017-02-15
影响因子：
10.6
通讯作者：
Kabbaj M
中科院分区：
文献类型：
--
作者：
Duclot F;Kabbaj M
由于重度抑郁症和双相情感障碍仍然是全球残疾的主要原因（1），迫切需要更有效的治疗方法，并更好地了解经典和新型抗抑郁药的作用机制。在过去的60年里，抑郁症的治疗依赖于单胺能神经传递的药理学靶向。然而，这种方法产生的疗效有限，超过50%的患者未能达到完全缓解（2），而在那些有反应的患者中，症状消退通常要经过数周至数月，这对自杀患者尤其构成显著风险。在过去的十年中，精神病学领域一直非常兴奋，因为许多临床研究表明，氯胺酮，一种非竞争性N-甲基-D-天冬氨酸受体拮抗剂，可以在治疗抵抗个体中诱导快速抗抑郁作用（3，4），伴随着这些患者亚组中自杀意念的减少（5）动物模型对于剖析经典和新型抗抑郁药治疗效果中涉及的潜在机制至关重要。一个这样的模型，这是在研究中使用的巴戈特等人。(6)是慢性社会失败压力。这种压力从行为学和生态学上的有效性中汲取力量，因为反复暴露于社会失败会产生持续的情绪压力而不会习惯化（7），大多数暴露于这种压力的动物对慢性而不是急性的经典抗抑郁治疗有反应（8）。这种动物模型的一个明显的额外优势是其在检查跨多个分子和行为终点的慢性压力的弹性和易感性的个体差异中的实用性。在一群连续10天处于社交失败的小鼠中，一部分有弹性的动物从未出现与类似压力的同类动物一样的明显的社交戒断症状，这些症状被称为“易感”。这项研究的有趣部分，增加了社会失败模型的有效性，是证明在这个易感人群中，一些小鼠对丙咪嗪或氯胺酮的抗抑郁药样作用有反应（反应者），而另一些则没有反应（无反应者）。在应答者和无应答者人群中，巴戈特等人(6)在与人类抑郁症相关的四个边缘系统区域进行了转录组测序，即前额叶皮层、杏仁核、杏仁核和海马体。值得注意的是，易感小鼠用抗抑郁药丙咪嗪和氯胺酮平行治疗，这导致了丰富的实验结果。
As major depressive and bipolar disorders continue to be leading causes of disability worldwide (1), there is an urgent need for more effective treatments and better understanding of the mechanisms of actions of classical and novel classes of antidepressants. For the past 60 years, the treatment of depression has relied on pharmacological targeting of monoaminergic neurotransmission. This approach, however, has yielded limited efficacy, with over 50% of patients failing to achieve full remission (2), while weeks to months often pass before symptoms subside in those who do respond—which poses a marked risk for suicidal patients in particular. Over the past decade, there has been great excitement in the field of psychiatry, as numerous clinical studies have shown that ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, can induce rapid antidepressant effects in treatment-resistant individuals (3, 4), with concomitant reduction of suicidal ideation in a subset of these patients (5).Animal models have been paramount to dissecting potential mechanisms implicated in the therapeutic effects of classical and novel antidepressants. One such model, which is used in the study by Bagot et al.(6), is chronic social defeat stress. This stress draws its strength from an ethological and ecological validity in that repeated exposure to social defeat generates persistent emotional stress without habituation (7), and most animals exposed to this stress respond to chronic, but not acute, classical antidepressant treatments (8). A clear additional advantage of this animal model is its utility in examining individual differences in resilience and susceptibility to chronic stress across multiple molecular and behavioral endpoints. In a population of mice exposed to 10 consecutive days of social defeat, a subset of resilient animals never develop the marked social withdrawal symptoms of their similarly stressed counterparts, which are termed “susceptible.” The interesting part of this study, which adds more validity to the social defeat model, is the demonstration that within this susceptible population, some mice respond to the antidepressant-like effects of imipramine or ketamine (responders) while others do not respond (nonresponders). In this population of responders and nonresponders, Bagot et al.(6) conducted transcriptome sequencing in four limbic regions associated with depression in humans, namely the prefrontal cortex, nucleus accumbens, amygdala, and hippocampus. Notably, susceptible mice were treated with the antidepressants imipramine and ketamine in parallel, which results in a rich experimental