Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Acta Pharmacol Sin. 2018 Apr;39(4):607-615. doi: 10.1038/aps.2017.138. Epub 2017 Dec 21.
Response inhibition is a critical executive control function in many species. Deficits in response inhibition have been observed in many disorders, eg, attention deficit/hyperactivity disorder (ADHD). The stop-signal task (SST) is a unique behavior task for evaluating response inhibition via measuring the covert latency of a stop process, and it is widely used in studies of humans, nonhuman primates and rodents. Methylphenidate (MPH; Ritalin) is a psychostimulant that is widely used for the treatment of ADHD and that effectively improves response inhibition in individuals with ADHD and normal subjects. However, its mechanism of improving response inhibition remains unknown. In this study we adopted a rodent nose-poking version of the SST to examine response inhibition by estimating the stop signal reaction time (SSRT) in rats. Administration of MPH (1 mg/kg, sc) 25 min before the SST test exerted a baseline-dependent effect of MPH on response inhibition, ie, it shortened the SSRTs only in the rats with larger baseline SSRTs, thereby improving response inhibition in these rats. The effect of MPH on response inhibition remained 3 h after MPH administration. Co-administration of PP2 (1 mg/kg, sc), a Src-protein tyrosine kinase (Src-PTKs) inhibitor that inhibited the upregulation of glutamate receptor expression on the plasma membrane of the prefrontal cortex (PFC), abolished the MPH-caused improvement in response inhibition. Furthermore, intra-PFC infusion of a selective AMPAR antagonist.NASPM (0.3 mmol/L, per side) via stainless guide cannulas implanted earlier abolished the effect of MPH on SSRT. These results suggest that AMPA receptors in the PFC are involved in the effect of MPH on response inhibition in rats.
反应抑制是许多物种中重要的执行控制功能。许多疾病，如注意力缺陷/多动障碍（ADHD），都存在反应抑制缺陷。停止信号任务（SST）是一种通过测量停止过程的隐蔽潜伏期来评估反应抑制的独特行为任务，广泛应用于人类、非人类灵长类动物和啮齿动物的研究。哌醋甲酯（MPH；利他林）是一种广泛用于治疗 ADHD 的精神兴奋剂，它能有效改善 ADHD 患者和正常受试者的反应抑制。然而，其改善反应抑制的机制尚不清楚。在这项研究中，我们采用了啮齿动物鼻触式 SST，通过估计大鼠的停止信号反应时间（SSRT）来检测反应抑制。在 SST 测试前 25 分钟给予 MPH（1mg/kg，sc），对反应抑制产生了一种依赖基线的 MPH 作用，即仅在基线 SSRT 较大的大鼠中缩短 SSRT，从而改善这些大鼠的反应抑制。MPH 对反应抑制的作用在 MPH 给药后 3 小时仍然存在。共给予 PP2（1mg/kg，sc），一种Src-蛋白酪氨酸激酶（Src-PTKs）抑制剂，抑制了前额叶皮质（PFC）质膜上谷氨酸受体表达的上调，消除了 MPH 引起的反应抑制改善。此外，通过先前植入的不锈钢导向套管，在 PFC 内输注选择性 AMPAR 拮抗剂.NASPM（0.3mmol/L，每侧），也消除了 MPH 对 SSRT 的影响。这些结果表明，PFC 中的 AMPAR 参与了 MPH 对大鼠反应抑制的作用。
