Takamatsu Y, Hagino Y, Sato A, Takahashi T, Nagasawa S Y, Kubo Y, Mizuguchi M, Uhl G R, Sora I, Ikeda K
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Curr Mol Med. 2015;15(3):245-52. doi: 10.2174/1566524015666150330144018.
The symptoms of attention-deficit/hyperactivity disorder (ADHD) are characterized by inattention and hyperactivity-impulsivity. It is a common childhood neurodevelopmental disorder that often persists into adulthood. Improvements in ADHD symptoms using psychostimulants have been recognized as a paradoxical calming effect. The psychostimulant methylphenidate (MPH) is currently used as the first-line medication for the management of ADHD. Recent studies have drawn attention to altered dopamine-mediated neurotransmission in ADHD, particularly reuptake by the dopamine transporter (DAT). This hypothesis is supported by the observation that DAT knockout mice exhibit marked hyperactivity that is responsive to acute MPH treatment. However, other behaviors relevant to ADHD have not been fully clarified. In the present study, we observed learning impairment in shuttle-box avoidance behavior together with hyperactivity in a novel environment in DAT knockout mice. Methylphenidate normalized these behaviors and enhanced escape activity in the tail suspension test. Interestingly, the effective dose of MPH increased extracellular dopamine in the prefrontal cortex but not striatum, suggesting an important role for changes in prefrontal dopamine in ADHD. Research that uses rodent models such as DAT knockout mice may be useful for elucidating the pathophysiology of ADHD.
注意力缺陷多动障碍（ADHD）的症状表现为注意力不集中以及多动冲动。它是一种常见的儿童神经发育障碍，常常持续至成年期。使用精神兴奋剂改善ADHD症状已被认为具有矛盾的镇静作用。精神兴奋剂哌甲酯（MPH）目前被用作治疗ADHD的一线药物。最近的研究已将注意力吸引到ADHD中多巴胺介导的神经传递改变上，尤其是多巴胺转运体（DAT）的再摄取。DAT基因敲除小鼠表现出对急性MPH治疗有反应的明显多动，这一观察结果支持了该假说。然而，与ADHD相关的其他行为尚未完全阐明。在本研究中，我们观察到DAT基因敲除小鼠在穿梭箱回避行为中存在学习障碍以及在新环境中存在多动。哌甲酯使这些行为恢复正常，并增强了悬尾试验中的逃避活动。有趣的是，MPH的有效剂量增加了前额叶皮质而非纹状体的细胞外多巴胺，这表明前额叶多巴胺变化在ADHD中起重要作用。使用诸如DAT基因敲除小鼠等啮齿动物模型的研究可能有助于阐明ADHD的病理生理学。
