Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
Neuropharmacology. 2019 Apr;148:178-188. doi: 10.1016/j.neuropharm.2019.01.003. Epub 2019 Jan 8.
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 K value 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.
儿茶酚胺递质多巴胺（DA）和去甲肾上腺素（NE）调节前额皮质（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药物对认知有显著影响。许多此类药物在临床上用于治疗注意力障碍。例如，哌甲酯阻断 DA 和 NE 的再摄取，是治疗注意力缺陷多动障碍（ADHD）的首选药物。最近，我们设计了 SK609-一种多巴胺 D3 受体（D3R）的选择性小分子激动剂。在这项研究中，我们进一步表征了 SK609 选择性抑制去甲肾上腺素转运体（NET）再摄取去甲肾上腺素的能力。我们的结果表明，SK609 以 500nM 的 K 值选择性抑制 NET，并作为 NET 底物。在未经处理的大鼠中，系统给予 SK609（4mg/kg；腹腔注射），通过微透析测量，PFC 中 NE 和 DA 分别增加 300%和 160%。基于这些神经化学结果，SK609 在大鼠的 PFC 依赖性、视觉引导的持续注意力任务中进行了测试。SK609 以剂量依赖性方式改善性能，呈经典的倒 U 型剂量反应函数，峰值作用在 4mg/kg。SK609 的峰值作用被 D2/D3R 拮抗剂氯丙嗪（0.05mg/kg；腹腔注射）或 alpha-1 肾上腺素受体拮抗剂特拉唑嗪（0.25mg/kg；腹腔注射）预处理阻断，证实 DA 和 NE 均在促进持续注意力中起作用。此外，SK609 在低表现动物中更显著地改善了持续注意力。与认知增强相关的 SK609 剂量（2、4 和 8mg/kg）不会引起自发运动活动增加，表明缺乏由多巴胺转运体（DAT）活性介导的副作用。这些结果表明，新型儿茶酚胺调节剂 SK609 有可能治疗持续注意力缺陷，而不会影响 DAT 活性，与安非他命和哌甲酯不同。
