Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Department of Psychiatry and Psychotherapy, Alexianer Krefeld GmbH, Krefeld, Germany.
Eur Arch Psychiatry Clin Neurosci. 2018 Sep;268(6):555-563. doi: 10.1007/s00406-018-0872-8. Epub 2018 Feb 5.
We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.
我们研究了氯氮平和氟哌啶醇这两种广泛用于治疗精神分裂症的药物对成年大鼠六个皮质和皮质下脑区基因表达的影响。药物治疗从出生后第 85 天开始，持续 12 周。10 只动物每天接受氟哌啶醇（1mg/kg 体重），10 只接受氯氮平（20mg/kg 体重）口服治疗。10 只对照大鼠未接受任何药物治疗。本研究选择的 10 个基因不属于多巴胺能或 5-羟色胺能系统，这两个系统通常是这两种物质的靶点，而是编码细胞骨架蛋白和突触递质释放机制的蛋白。在额前皮质、扣带回（CG1）和尾壳核以及海马角状回 1（CA1）、角状回 3（CA3）和齿状回进行了定量实时 PCR。结果表明，两种药物的作用下存在明显的基因表达模式，但也存在依赖于脑区的不同基因调控。与对照组相比，氟哌啶醇治疗的动物在 CA3 中 SNAP-25 的表达显著下调（p=0.0134），在 CA1 中 STX1A 的表达显著上调（p=0.0133）。氯氮平治疗的动物在 CG1 中 SNAP-25 的表达显著下调（p=0.0013）。我们的研究结果清楚地表明，药物的作用在不同的脑区之间存在差异。这些影响可能是通过药物靶向的蛋白质的反馈机制间接介导的，但不能排除氟哌啶醇或氯氮平对基因表达机制的直接作用。
