Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Yamaguchi University, Yamaguchi, Japan.
Mol Psychiatry. 2021 Sep;26(9):4958-4967. doi: 10.1038/s41380-020-0784-7. Epub 2020 May 21.
Alterations in the cortical dopamine system and microglial activation have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), one of neurodevelopmental disorders that can be conventionally treated with a dopamine enhancer (methylphenidate) albeit unsatisfactorily. Here, we investigated the contributions of the dopamine D1 receptor (D1R) and activated microglia and their interactions to the clinical severities in ADHD individuals using positron emission tomography (PET). Twenty-four psychotropic-naïve ADHD individuals and 24 age- and sex-matched typically developing (TD) subjects underwent PET measurements with [C]SCH23390 for the D1R and CPK11195 for activated microglia as well as assessments of clinical symptoms and cognitive functions. The ADHD individuals showed decreased D1R in the anterior cingulate cortex (ACC) and increased activated microglia in the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) compared with the TD subjects. The decreased D1R in the ACC was associated with severe hyperactivity in the participants with ADHD. Microglial activation in the DLPFC were associated with deficits in processing speed and attentional ability, and that in the OFC was correlated with lower processing speed in the ADHD individuals. Furthermore, positive correlations between the D1R and activated microglia in both the DLPFC and the OFC were found to be significantly specific to the ADHD group and not to the TD group. The current findings suggest that microglial activation and the D1R reduction as well as their aberrant interactions underpin the neurophysiological mechanism of ADHD and indicate these biomolecular changes as a novel therapeutic target.
皮质多巴胺系统和小胶质细胞激活的改变与注意缺陷多动障碍（ADHD）的病理生理学有关，ADHD 是一种神经发育障碍，传统上可以用多巴胺增强剂（哌甲酯）治疗，但效果不尽如人意。在这里，我们使用正电子发射断层扫描（PET）研究了多巴胺 D1 受体（D1R）和激活的小胶质细胞及其相互作用对 ADHD 个体临床严重程度的贡献。24 名未经精神药物治疗的 ADHD 个体和 24 名年龄和性别匹配的典型发育（TD）个体接受了 [C]SCH23390 用于 D1R 和 [C]（R）PK11195 用于激活小胶质细胞的 PET 测量，以及临床症状和认知功能的评估。与 TD 个体相比，ADHD 个体的前扣带回皮层（ACC）中的 D1R 减少，而背外侧前额叶皮层（DLPFC）和眶额皮层（OFC）中的激活小胶质细胞增加。ACC 中的 D1R 减少与 ADHD 患者的严重多动有关。DLPFC 中的小胶质细胞激活与处理速度和注意力能力缺陷有关，OFC 中的小胶质细胞激活与 ADHD 个体的处理速度降低有关。此外，还发现 DLPFC 和 OFC 中 D1R 和激活小胶质细胞之间的正相关仅在 ADHD 组中显著特异性，而不在 TD 组中显著特异性。目前的研究结果表明，小胶质细胞激活和 D1R 减少以及它们的异常相互作用是 ADHD 的神经生理学机制的基础，并表明这些生物分子变化是一种新的治疗靶点。
