Pharmacology and Neuroscience Research Group, Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
Pharmacology and Neuroscience Research Group, Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
Neurochem Int. 2019 Mar;124:193-199. doi: 10.1016/j.neuint.2019.01.016. Epub 2019 Jan 17.
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 D 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 D. 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.
哌甲酯（MPH）是治疗儿童注意力缺陷多动障碍（ADHD）的主要药物。众所周知，MPH 可急性阻断多巴胺（DAT）和去甲肾上腺素（NET）转运体。然而，其对其他儿茶酚胺靶点的影响知之甚少。本研究旨在比较急性（2mg/kg，腹腔注射）和慢性（2mg/kg，每日两次，共 2 周）MPH 治疗对年轻大鼠大脑中与 ADHD 症状和治疗相关的关键儿茶酚胺蛋白靶点的影响。为此，在额皮质（FC）、顶皮质（PCx）和背侧纹状体（DS）和腹侧纹状体（VS）中测量了 DAT、NET、囊泡单胺转运体 2（VMAT2）、儿茶酚胺合成限速酶酪氨酸羟化酶（TH）和多巴胺 D 受体的密度。数据表明，MPH 的作用取决于治疗持续时间和研究的脑区。除了 VS 中的 DAT 外，我们的结果表明，慢性而非急性给予 MPH 会增加 DAT、NET、TH、VMAT2 和 D 的水平。这些影响在 VS 中比 DS 更明显，在 PCx 中比 FC 更明显。此外，慢性 MPH 增强了左 DS 中的 DAT 水平，但右 DS 中没有。总之，这项研究提供了新的证据，表明慢性 MPH 对幼年大鼠优先改变 PCx 和 VS 中的儿茶酚胺靶点，而不是 DS 和 FC。慢性 MPH 增加 DAT、NET 和 VMAT2 的水平表明，该药物可能会长期失去其部分急性作用，以增加多巴胺和去甲肾上腺素的细胞外水平。总之，这些发现为 MPH 在治疗 ADHD 中的作用机制提供了新的见解，并进一步表明兴奋剂药物的长期疗效可能有限。
