Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Neuropharmacology. 2019 Sep 15;156:107547. doi: 10.1016/j.neuropharm.2019.02.029. Epub 2019 Feb 22.
The selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine have been considered to involve activation of postsynaptic α2A adrenoceptor in frontal pyramidal neurons. However, the effects of chronic guanfacine administration on catecholaminergic transmissions associated with the orbitofrontal cortex (OFC) remain unclear. To explore the mechanisms of action of guanfacine on catecholaminergic transmission, the effects of its acute local or sub-chronic systemic administration on catecholamine release within pathways from locus coeruleus (LC) to OFC and reticular thalamic nucleus (RTN), from RTN to mediodorsal thalamic nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Acute OFC local administration of guanfacine did not affect catecholamine release in OFC. Acute LC local and sub-chronic systemic administrations of guanfacine reduced norepinephrine release in LC, OFC and RTN, and also reduced GABA release in MDTN, whereas AMPA-induced (perfusion with AMPA into NDTN) releases of l-glutamate, norepinephrine and dopamine in OFC were enhanced by sub-chronic systemic guanfacine administration. This study identified that catecholaminergic transmission is composed of three pathways: direct noradrenergic and co-releasing catecholaminergic LC-OFC pathways and intermediate LC-OFC (LC-RTN-MDTN-OFC) pathway. We demonstrated the dual actions of guanfacine on catecholaminergic transmission: attenuation of direct noradrenergic LC-OFC transmission at the resting stage and enhancement of direct co-releasing catecholaminergic LC-OFC transmission via GABAergic disinhibition in the intermediate LC-OFC pathway. These dual actions of guanfacine probably contribute to clinical actions of guanfacine against ADHD and its comorbid symptoms. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
选择性 α2A 肾上腺素受体激动剂胍法辛可减少注意力缺陷多动障碍（ADHD）患者的多动症状并改善认知障碍。胍法辛的主要机制被认为涉及到激活额叶锥体神经元上的突触后 α2A 肾上腺素受体。然而，慢性胍法辛给药对与眶额皮层（OFC）相关的儿茶酚胺传递的影响尚不清楚。为了探讨胍法辛对儿茶酚胺传递的作用机制，使用超高效液相色谱法的多探针微透析法测定了其急性局部或亚慢性全身给药对蓝斑核（LC）至 OFC 和网状丘脑核（RTN）、RTN 至中脑背侧丘脑核（MDTN）以及 MDTN 至 OFC 通路儿茶酚胺释放的影响。急性 OFC 局部给予胍法辛不会影响 OFC 中的儿茶酚胺释放。急性 LC 局部和亚慢性全身给予胍法辛可减少 LC、OFC 和 RTN 中的去甲肾上腺素释放，还可减少 MDTN 中的 GABA 释放，而亚慢性全身给予胍法辛可增强 AMPA 诱导（将 AMPA 灌注到 NDTN）引起的 OFC 中 l-谷氨酸、去甲肾上腺素和多巴胺的释放。本研究确定了儿茶酚胺传递由三条通路组成：直接去甲肾上腺素能和共释放儿茶酚胺能 LC-OFC 通路和中间 LC-OFC（LC-RTN-MDTN-OFC）通路。我们证明了胍法辛对儿茶酚胺传递的双重作用：在静息状态下减弱直接去甲肾上腺素能 LC-OFC 传递，通过中间 LC-OFC 通路中的 GABA 能抑制作用增强直接共释放儿茶酚胺能 LC-OFC 传递。胍法辛的这两种作用可能有助于其治疗 ADHD 及其共病症状的临床作用。本文是特刊“攻击性和冲动性的神经生物学现状”的一部分。
