Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University Hospital Frankfurt, Deutschordenstrasse 50, 60528 Frankfurt am Main, Germany.
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:221-8. doi: 10.1016/j.pnpbp.2012.08.012. Epub 2012 Aug 30.
Atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, is a non-stimulant approved for the treatment of attention deficit/hyperactivity disorder (ADHD). Little is known about the molecular basis for its therapeutic effect. The objective of this animal study was to determine alterations in gene expression patterns in the prefrontal cortex after long-term administration of atomoxetine. Rats were treated for 21 days during childhood and early adolescent stages of development with a once-daily oral application of 0.05 g/kg atomoxetine, which resulted in plasma levels similar to those described in children. A whole genome RNA-microarray of rat prefrontal cortical gene expression after administration of atomoxetine versus sterile water revealed an mRNA increase in 114 genes (≥2-fold) while 11 genes were down-regulated (≤0.5-fold). By applying quantitative real-time PCR (qRT-PCR) and Western Blot we confirmed a significant increase in the expression of GABA A receptor subunits as well as ubiquinol-cytochrome c reductase complex core protein 2 (Uqcrc2). SNAP-25 (synaptosomal-associated protein of 25 kDa), which is an ADHD candidate gene and an important vesicle protein involved in axonal growth, synaptic plasticity and regulation of neurotransmitter release was also significantly upregulated on RNA- and protein level after atomoxetine treatment. In summary, we could show that long-term treatment with the ADHD drug atomoxetine induces the regulation of several genes in the prefrontal cortex of young rats. Especially the increased expression of SNAP-25 and GABA-A receptor subunits may indicate additional active therapeutic mechanisms for atomoxetine.
托莫西汀（ATX）是一种选择性去甲肾上腺素再摄取抑制剂，是一种非兴奋剂，用于治疗注意力缺陷/多动障碍（ADHD）。对于其治疗效果的分子基础知之甚少。本动物研究的目的是确定长期给予托莫西汀后前额叶皮层的基因表达模式的改变。在儿童和青少年发育的早期阶段，大鼠每天接受一次口服 0.05g/kg 的托莫西汀治疗 21 天，这导致了与儿童中描述的相似的血浆水平。给予托莫西汀与无菌水相比，大鼠前额叶皮质基因表达的全基因组 RNA 微阵列显示 114 个基因的 mRNA 增加（≥2 倍），而 11 个基因下调（≤0.5 倍）。通过应用定量实时 PCR（qRT-PCR）和 Western Blot，我们证实了 GABA A 受体亚基以及泛醌-细胞色素 c 还原酶核心蛋白 2（Uqcrc2）的表达显著增加。突触相关蛋白 25kDa（SNAP-25）是 ADHD 的候选基因，也是参与轴突生长、突触可塑性和神经递质释放调节的重要囊泡蛋白，在给予托莫西汀后，其 RNA 和蛋白质水平也显著上调。总之，我们可以表明，长期使用 ADHD 药物托莫西汀会诱导年轻大鼠前额叶皮层中几个基因的调节。特别是 SNAP-25 和 GABA-A 受体亚基的表达增加可能表明托莫西汀的额外有效治疗机制。
