The psychostimulant methylphenidate (MPH) is the primary drug treatment for attention deficit hyperactivity disorder (ADHD) in children. MPH is well known to acutely block the dopamine (DAT) and noradrenaline (NET) transporters. Its effect on additional catecholamine targets is however less known. This study was aimed at comparing the effects of acute (2 mg/kg, i.p.) and chronic (2 mg/kg twice daily for 2 weeks) MPH treatment to young rats on key catecholamine protein targets in brain regions implicated in the symptoms and treatment of ADHD. For this purpose, the density of DAT, NET, the vesicular monoamine transporter 2 (VMAT2), the rate limiting enzyme for catecholamine synthesis tyrosine hydroxylase (TH) and the dopamine D1 receptor were measured in frontal (FC), parietal cortex (PCx) and the dorsal (DS) and ventral (VS) striatum. The data demonstrate that the effects of MPH depend on duration of treatment and brain region investigated. With the exception of DAT in the VS our results indicate that chronic but not acute administration of MPH increases levels of DAT, NET, TH, VMAT2 and D1. These effects were further more prominent in the VS over DS and in the PCx compared to the FC. In addition, chronic MPH enhanced DAT levels in the left DS but not in right side. To summarize, this study shows new evidence that chronic MPH to young rats preferentially alters catecholamine targets in PCx and VS over DS and FC. The effect of chronic MPH to increase levels of DAT, NET and VMAT2 suggests that the drug might long-term loose some of its acute action to increase extracellular levels of dopamine and noradrenaline. In conclusion, these findings provide novel insights into the mechanism of action by MPH in the treatment of ADHD and further suggest that the long-term effectiveness of the stimulant drug could be limited.

中文翻译：

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慢性哌醋甲酯可优先改变顶叶皮质和腹侧纹状体中的儿茶酚胺蛋白靶标。

精神兴奋药哌醋甲酯（MPH）是儿童注意力缺陷多动障碍（ADHD）的主要药物治疗方法。众所周知，MPH会严重阻断多巴胺（DAT）和去甲肾上腺素（NET）转运蛋白。然而，它对其他儿茶酚胺靶的作用尚不为人所知。这项研究旨在比较急性（2 mg / kg，ip）和慢性（2 mg / kg每天两次，连续2周）对年轻大鼠的MPH治疗对涉及症状和治疗的大脑区域关键儿茶酚胺蛋白靶标的影响多动症。为此，在额叶（FC），顶叶皮质（PCx）中测量DAT，NET，水泡单胺转运蛋白2（VMAT2），儿茶酚胺合成酪氨酸羟化酶（TH）的限速酶和多巴胺D1受体的密度。以及背侧（DS）和腹侧（VS）纹状体。数据表明，MPH的作用取决于治疗的持续时间和所研究的大脑区域。除了VS中的DAT以外，我们的研究结果表明，长期但非急性MPH给药会增加DAT，NET，TH，VMAT2和D1的水平。与FC相比，在DS上的VS和PCx中，这些效果更加突出。此外，慢性MPH增强了左DS而不是右侧的DAT水平。总而言之，这项研究显示了新的证据，即年轻大鼠的慢性MPH优先改变PCx和VS中的儿茶酚胺靶标，而不是DS和FC。慢性MPH会增加DAT，NET和VMAT2的水平，这表明该药物可能会长期失去某些急性作用，从而增加细胞内多巴胺和去甲肾上腺素的水平。综上所述，