Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex
Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex
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急性和亚慢性服用胍法辛对眶额皮质儿茶酚胺能传递的影响
DOI：
10.1016/j.neuropharm.2019.02.029
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发表时间：
2019
影响因子：
4.7
通讯作者：
Ueda Yuto
中科院分区：
文献类型：
--
作者：
Okada Motohiro;Fukuyama Kouji;Kawano Yasuhiro;Shiroyama Takashi;Suzuki Dai;Ueda Yuto
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）患者的多动并改善认知障碍。胍法辛的主要作用机制被认为与激活额叶锥体神经元突触后α2A肾上腺素能受体有关。然而，长期服用胍法辛对与眶额皮质（OFC）相关的儿茶酚胺能传递的影响尚不清楚。为探讨胍法辛对儿茶酚胺能神经递质传递的作用机制，采用多探针微透析-超高效液相色谱法，观察了胍法辛急性局部或亚慢性全身给药对蓝斑（LC）-眶额皮层（OFC）和丘脑网状核（RTN）、丘脑背内侧核（MDTN）和丘脑背内侧核（MDTN）-眶额皮层（OFC）通路中儿茶酚胺释放的影响。急性OFC局部应用胍法辛不影响OFC中儿茶酚胺的释放。急性LC局部和亚慢性全身给予胍法辛减少LC、OFC和RTN中的去甲肾上腺素释放，并且还减少MDTN中的GABA释放，而AMPA诱导的（将AMPA灌注到NDTN中）OFC中的谷氨酸、去甲肾上腺素和多巴胺的释放被亚慢性全身给予胍法辛增强。本研究发现，儿茶酚胺能传递由三条途径组成：直接去甲肾上腺素能和共释放儿茶酚胺能LC-OFC途径和中间LC-OFC途径（LC-RTN-MDTN-OFC）。我们证明了胍法辛对儿茶酚胺能传递的双重作用：在静息阶段减弱直接去甲肾上腺素能LC-OFC传递，并通过中间LC-OFC通路中的GABA能去抑制增强直接共释放的儿茶酚胺能LC-OFC传递。胍法辛的这些双重作用可能有助于胍法辛对ADHD及其共病症状的临床作用。这篇文章是题为“侵略和冲动的神经生物学现状”的特刊的一部分。
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 ofl-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’.