Jung Da Hee, Lee Hong Ju, Choi Young Whan, Shin Hwa Kyoung, Choi Byung Tae
Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; Graduate Training Program of Korean Medical Therapeutics for Healthy Aging, Pusan National University, Yangsan 50612, Republic of Korea.
Department of Horticultural Bioscience, College of Natural Resource and Life Science, Pusan National University, Miryang 50463, Republic of Korea.
Biomed Pharmacother. 2023 Apr;160:114352. doi: 10.1016/j.biopha.2023.114352. Epub 2023 Feb 2.
The etiology of attention-deficit hyperactivity disorder (ADHD) strongly suggests a genetic component as the main cause; however, environmental factors such as early adverse experiences in childhood may play an interactive role with the genetic susceptibility. Spontaneously hypertensive rats (SHRs), a genetic ADHD model, and control Wistar Kyoto rats (WKYs) were subjected to chronic unpredictable mild stress during the juvenile period. The behavioral characteristics were monitored, and dopamine-related factors in the core regions of dopaminergic pathways were measured. Higher ADHD symptom-related behaviors were observed in response to juvenile stress in male SHRs than control WKYs. For the SHRs subjected to juvenile stress, hyperactivity in males, recognition in females, and depressant potential in both sexes were markedly observed. In the expression of 17 dopamine-related genes and proteins, greater changes were detected in male SHRs subjected to juvenile stress, especially in dopamine metabolic factors. Dopamine clearance factors involved in dopamine degradation and transport, especially catechol-O-methyltransferase (COMT) and dopamine transporter (DAT), showed sex-specific differences induced by juvenile stress in dopamine metabolite assays. Moreover, stressed male SHRs treated with methylphenidate showed better improvement in behavior than the females, resulting in different levels of COMT and DAT amelioration. These results suggest that juvenile stress potentially increased the incidence of ADHD in a genetic rat model, which showed sex-specific differences based on the expression of COMT and DAT. Therefore, our results could help develop gender-specific diagnostics and healthcare options for juvenile stress in patients with ADHD.
注意缺陷多动障碍（ADHD）的病因强烈提示遗传因素是主要原因；然而，童年早期不良经历等环境因素可能与遗传易感性相互作用。自发性高血压大鼠（SHRs）作为一种遗传性ADHD模型，与对照Wistar Kyoto大鼠（WKYs）在幼年期接受慢性不可预测的轻度应激。监测其行为特征，并测量多巴胺能通路核心区域的多巴胺相关因子。与对照WKYs相比，雄性SHRs在幼年应激后出现了更多与ADHD症状相关的行为。对于经历幼年应激的SHRs，明显观察到雄性的多动、雌性的认知以及两性的抑制潜能。在17种多巴胺相关基因和蛋白质的表达中，幼年应激的雄性SHRs出现了更大的变化，尤其是在多巴胺代谢因子方面。参与多巴胺降解和转运的多巴胺清除因子，特别是儿茶酚-O-甲基转移酶（COMT）和多巴胺转运体（DAT），在多巴胺代谢物检测中显示出幼年应激诱导的性别特异性差异。此外，用哌甲酯治疗的应激雄性SHRs在行为上的改善比雌性更好，导致COMT和DAT的改善水平不同。这些结果表明，幼年应激可能增加了遗传性大鼠模型中ADHD的发病率，基于COMT和DAT的表达显示出性别特异性差异。因此，我们的结果有助于为ADHD患者的幼年应激开发性别特异性的诊断和医疗方案。
