Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.
Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.
复制标题
选择性激活多巴胺 D3 受体和去甲肾上腺素转运蛋白阻断可增强持续注意力。
DOI：
10.1016/j.neuropharm.2019.01.003
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发表时间：
2019
影响因子：
4.7
通讯作者：
Kortagere,Sandhya
中科院分区：
文献类型：
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作者：
Marshall,CourtneyA;Brodnik,ZacharyD;Mortensen,OleV;Reith,MaartenEA;Shumsky,JedS;Waterhouse,BarryD;España,RodrigoA;Kortagere,Sandhya
多巴胺（DA）和去甲肾上腺素（NE）调节前额叶皮层（PFC）回路活动和PFC介导的执行功能。因此，影响儿茶酚胺神经传递的药理学试剂对认知产生显著影响。许多这样的药剂在临床上用于治疗注意力障碍。例如，哌甲酯阻断DA和NE再摄取，是注意缺陷多动障碍（ADHD）治疗的主要选择。最近，我们设计了SK 609-DA D3受体（D3 R）的选择性小分子激动剂。在这项研究中，我们进一步表征了SK 609选择性抑制NE转运蛋白（NET）对NE的再摄取的能力。我们的研究结果表明，SK 609选择性抑制NET的Ki值为1.500 nM，并表现为NET底物。全身给药SK 609（4 mg/kg; i. p.）在幼稚大鼠中，通过微透析测量，PFC中的NE和DA分别增加了300%和160%。基于这些神经化学的结果，SK 609在大鼠中的PFC依赖的、视觉引导的持续注意任务中进行了测试。SK 609以剂量依赖性方式改善性能，具有经典的倒U型剂量反应函数，在4 mg/kg时达到峰值效应。SK 609的峰值效应被D2/D3 R拮抗剂雷氯必利（0.05 mg/kg; i.p）或α-1肾上腺素能受体拮抗剂哌唑嗪（0.25 mg/kg; i.p）预处理阻断，证实了DA和NE在促进持续注意力方面的作用。此外，SK 609在表现差的动物中更显着地改善了持续注意力。与认知增强相关的SK 609剂量（2、4和8 mg/kg）未引起自发运动活动增加，表明缺乏DA转运蛋白（DAT）活性介导的副作用。这些结果表明，新的儿茶酚胺能调节剂SK 609具有治疗持续性注意力缺陷而不影响DAT活性的潜力，将其与安非他明和哌甲酯区分开来。
Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 – a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Kivalue of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naïve rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.