Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects
Mice lacking the immediate early gene Egr3 respond to the anti-aggressive effects of clozapine yet are relatively resistant to its sedating effects
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DOI：
10.1038/sj.npp.1301505
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发表时间：
2008-05-01
影响因子：
7.6
通讯作者：
Milbrandt, Jeffrey
中科院分区：
文献类型：
--
作者：
Gallitano-Mendel, Amelia;Wozniak, David F.;Milbrandt, Jeffrey
早期生长反应基因 (Egr) 家族的立即早期基因 (IEG) 在大脑中被激活，以响应压力、社会刺激和精神活性药物的使用。然而，人们对这些基因在对这些刺激的生物或行为反应中的作用知之甚少。在这里，我们发现，缺乏 IEG 转录因子 Egr3 的小鼠（Egr3-/-小鼠）在应对外来入侵者的压力性社会刺激时表现出更强的攻击性，并且攻击潜伏期缩短。结合我们对同种动物进行持续性和侵入性嗅觉介导的社会调查的结果，这些结果表明 Egr3-/- 小鼠的冲动性增加。我们还表明，长期服用抗精神病药物氯氮平可以显着抑制 Egr3-/- 小鼠的攻击性。尽管 Egr3-/- 小鼠对氯氮平的这种治疗作用敏感，但与 WT 同窝对照小鼠相比，它们对急性氯氮平的镇静作用表现出明显的抵抗力。这表明氯氮平的治疗、抗攻击作用与其镇静活性是分开的，并且Egr3缺失导致的生物学异常区分了这些不同的机制。因此，Egr3-/-小鼠可能为阐明氯氮平的作用机制以及理解攻击行为背后的生物学提供重要工具。值得注意的是，与非精神病对照组相比，精神分裂症患者对抗精神病药物副作用的敏感性相似降低，尽管药物产生了治疗反应。这表明 Egr3-/- 小鼠可能有助于深入了解精神分裂症的神经生物学异常。
Immediate early genes (IEGs) of the early growth response gene (Egr) family are activated in the brain in response to stress, social stimuli, and administration of psycho-active medications. However, little is known about the role of these genes in the biological or behavioral response to these stimuli. Here we show that mice lacking the IEG transcription factor Egr3 (Egr3-/-mice) display increased aggression, and a decreased latency to attack, in response to the stressful social stimulus of a foreign intruder. Together with our findings of persistent and intrusive olfactory-mediated social investigation of conspecifics, these results suggest increased impulsivity in Egr3-/-mice. We also show that the aggression of Egr3-/- mice is significantly inhibited with chronic administration of the antipsychotic medication clozapine. Despite their sensitivity to this therapeutic effect of clozapine, Egr3-/- mice display a marked resistance to the sedating effects of acute clozapine compared with WT littermate controls. This indicates that the therapeutic, anti-aggressive action of clozapine is separable from its sedating activity, and that the biological abnormality resulting from loss of Egr3 distinguishes these different mechanisms. Thus Egr3-/- mice may provide an important tool for elucidating the mechanism of action of clozapine, as well as for understanding the biology underlying aggressive behavior. Notably, schizophrenia patients display a similar decreased susceptibility to the side effects of antipsychotic medications compared to non-psychiatric controls, despite the medications producing a therapeutic response. This suggests the possibility that Egr3-/- mice may provide insight into the neurobiological abnormalities underlying schizophrenia.