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首页> 外文期刊>Journal of Molecular Psychiatry >Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis
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Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

机译：奥氮平诱导的DNA甲基化变化支持精神病的多巴胺假说

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BackgroundThe dopamine (DA) hypothesis of schizophrenia proposes the mental illness is caused by excessive transmission of dopamine in selected brain regions. Multiple lines of evidence, including blockage of dopamine receptors by antipsychotic drugs that are used to treat schizophrenia, support the hypothesis. However, the dopamine D2 receptor ( DRD2 ) blockade cannot explain some important aspects of the therapeutic effect of antipsychotic drugs. In this study, we hypothesized that antipsychotic drugs could affect the transcription of genes in the DA pathway by altering their epigenetic profile. MethodsTo test this hypothesis, we examined the effect of olanzapine, a commonly used atypical antipsychotic drug, on the DNA methylation status of genes from DA neurotransmission in the brain and liver of rats . Genomic DNA isolated from hippocampus, cerebellum, and liver of olanzapine treated ( n =?2) and control ( n =?2) rats were analyzed using rat specific methylation arrays. ResultsOur results show that olanzapine causes methylation changes in genes encoding for DA receptors ( dopamine D1 receptor, dopamine D2 receptor and dopamine D5 receptor), a DA transporter (solute carrier family 18 member 2), a DA synthesis (differential display clone 8), and a DA metabolism (catechol-O-methyltransferase) . We assessed a total of 40 genes in the DA pathway and found 19 to be differentially methylated between olanzapine treated and control rats. Most (17/19) genes showed an increase in methylation, in their promoter regions with in silico analysis strongly indicating a functional potential to suppress transcription in the brain. ConclusionOur results suggest that chronic olanzapine may reduce DA activity by altering gene methylation. It may also explain the delayed therapeutic effect of antipsychotics, which occurs despite rapid dopamine blockade. Furthermore, given the common nature of epigenetic variation, this lends insight into the differential therapeutic response of psychotic patients who display adequate blockage of dopamine receptors.
机译：背景精神分裂症的多巴胺（DA）假说提出精神疾病是由于多巴胺在特定大脑区域的过度传播引起的。有多种证据支持这一假说，其中包括用于治疗精神分裂症的抗精神病药对多巴胺受体的阻断。但是，多巴胺D2受体（DRD2）的阻滞不能解释抗精神病药治疗作用的一些重要方面。在这项研究中，我们假设抗精神病药可以通过改变其表观遗传特性来影响DA通路中基因的转录。方法为了检验这一假设，我们检查了奥氮平（一种常用的非典型抗精神病药）对大鼠脑和肝脏中DA神经传递基因DNA甲基化状态的影响。使用大鼠特异性甲基化阵列分析了从奥氮平治疗（n =？2）和对照（n =？2）大鼠的海马，小脑和肝脏分离的基因组DNA。结果我们的结果表明，奥氮平会导致编码DA受体（多巴胺D1受体，多巴胺D2受体和多巴胺D5受体），DA转运蛋白（溶质载体家族18个成员2），DA合成（差异展示克隆8）的基因甲基化变化，和DA代谢（儿茶酚-O-甲基转移酶）。我们评估了DA通路中总共40个基因，发现19个在奥氮平治疗组和对照组之间差异甲基化。大多数（17/19）基因在其启动子区域显示甲基化增强，计算机分析结果强烈显示了抑制大脑转录的功能潜力。结论我们的结果表明，慢性奥氮平可能通过改变基因甲基化而降低DA活性。它也可以解释抗精神病药的延迟治疗作用，尽管多巴胺迅速被阻断，但这种作用仍然发生。此外，鉴于表观遗传变异的共同性质，这使人们对表现出足够的多巴胺受体阻滞作用的精神病患者的不同治疗反应有了更深入的了解。

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