School of Life Sciences, Arizona State University, Tempe, AZ, USA.
Neuropsychopharmacology. 2012 Sep;37(10):2285-98. doi: 10.1038/npp.2012.81. Epub 2012 Jun 13.
The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported that Egr3-deficient (Egr3(-/-)) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect in Egr3(-/-) mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity of Egr3(-/-) and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT(2A)R) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity of Egr3(-/-) mice. Radioligand binding revealed nearly 70% reduction in 5HT(2A)R expression in the prefrontal cortex of Egr3(-/-) mice compared with controls. Egr3(-/-) mice also exhibit a decreased head-twitch response to 5HT(2A)R agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity of Egr3(-/-) mice to the locomotor suppressive effects of SGAs, and suggest that 5HT(2A)Rs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT(2A)R in Egr3(-/-) mice aligns with numerous studies reporting decreased 5HT(2A)R levels in the brains of schizophrenia patients, and the gene encoding the 5HT(2A)R is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction in EGR3 in humans may influence risk for schizophrenia.
早期生长反应基因 3（Egr3）与精神分裂症有关，在死后患者的大脑中表达水平降低。我们之前报道过，与野生型（WT）同窝仔相比，Egr3 缺陷（Egr3(-/-)）小鼠对氯氮平的镇静作用的敏感性降低，这与精神分裂症患者对抗精神病药物副作用的耐受性增加相平行。在这项研究中，我们使用了一种药理学剖析方法来鉴定 Egr3(-/-)小鼠中的神经递质受体缺陷，该缺陷可能介导它们对氯氮平的运动抑制作用的抗性。我们报告说，这种反应是第二代抗精神病药物（SGAs）特有的，因为第一代药物对 Egr3(-/-)和 WT 小鼠的运动活性具有相似的抑制作用。此外，与氯氮平镇静作用源自抗组胺作用的主导理论相反，我们表明 H1 组胺受体在 C57BL/6 小鼠中不是这种作用的原因。相反，选择性 5-羟色胺 2A 受体（5HT(2A)R）拮抗剂酮色林和 MDL-11939 复制了 SGAs 的作用，以一种未能抑制 Egr3(-/-)小鼠活性的剂量抑制 WT 小鼠的活性。放射性配体结合显示，与对照组相比，Egr3(-/-)小鼠前额叶皮层中的 5HT(2A)R 表达减少近 70%。Egr3(-/-)小鼠还表现出对 5HT(2A)R 激动剂 1-(2,5-二甲氧基-4-碘苯)-2-氨基丙烷（DOI）的摇头反应减少。这些发现提供了一种机制来解释 Egr3(-/-)小鼠对 SGAs 的运动抑制作用的敏感性降低，并且表明 5HT(2A)R 也可能导致这些药物在人类中的镇静作用。此外，由于 Egr3(-/-)小鼠皮质 5HT(2A)R 的缺陷与许多报道精神分裂症患者大脑中 5HT(2A)R 水平降低的研究相吻合，并且编码 5HT(2A)R 的基因本身就是一个主要的精神分裂症候选基因，这些发现表明了一种潜在的机制，即人类中 EGR3 的潜在功能障碍可能影响精神分裂症的风险。
