Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:264-276. doi: 10.1016/j.pnpbp.2018.12.004. Epub 2018 Dec 6.
Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, aberrant impulsivity, and hyperactivity. Although the underlying pathophysiology of ADHD remains unclear, dopamine and norepinephrine signaling originating from the ventral tegmental area (VTA) and locus coeruleus (LC) is thought to be critically involved. In this study, we employ Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) together with the mouse 5-Choice Serial Reaction Time Task (5-CSRTT) to investigate the necessary roles of these catecholamines in ADHD-related behaviors, including attention, impulsivity, and motivation. By selective inhibition of tyrosine hydroxylase (TH)-positive VTA dopamine neurons expressing the Gi-coupled DREADD (hM4Di), we observed a marked impairment of effort-based motivation and subsequently speed and overall vigor of responding. At the highest clozapine N-oxide (CNO) dose tested (i.e. 2 mg/kg) to activate hM4Di, we detected a reduction in locomotor activity. DREADD-mediated inhibition of LC norepinephrine neurons reduced attentional performance in a variable stimulus duration test designed to increase task difficulty, specifically by increasing trials omissions, reducing mean score, and visual processing speed. These findings show that VTA dopamine and LC norepinephrine neurons differentially affect attention, impulsive and motivational control. In addition, this study highlights how molecular genetic probing of selective catecholamine circuits can provide valuable insights into the mechanisms underlying ADHD-relevant behaviors.
注意缺陷多动障碍（ADHD）是一种精神障碍，其特征为注意力不集中、行为冲动和活动过度。尽管 ADHD 的潜在病理生理学机制仍不清楚，但来自腹侧被盖区（VTA）和蓝斑核（LC）的多巴胺和去甲肾上腺素信号被认为是至关重要的。在这项研究中，我们采用 Designer Receptor Exclusively Activated by Designer Drugs（DREADD）与小鼠 5-Choice Serial Reaction Time Task（5-CSRTT）相结合，来研究这些儿茶酚胺在 ADHD 相关行为中的必要作用，包括注意力、冲动性和动机。通过对表达 Gi 偶联 DREADD（hM4Di）的酪氨酸羟化酶（TH）阳性 VTA 多巴胺神经元进行选择性抑制，我们观察到基于努力的动机以及随后的反应速度和整体活力显著受损。在测试的最高氯氮平 N-氧化物（CNO）剂量（即 2mg/kg）激活 hM4Di 时，我们检测到运动活性降低。DREADD 介导的 LC 去甲肾上腺素神经元抑制降低了在设计用于增加任务难度的可变刺激持续时间测试中的注意力表现，具体表现为增加试验遗漏、降低平均得分和视觉处理速度。这些发现表明 VTA 多巴胺和 LC 去甲肾上腺素神经元对注意力、冲动和动机控制有不同的影响。此外，这项研究强调了选择性儿茶酚胺回路的分子遗传探测如何为 ADHD 相关行为的机制提供有价值的见解。
