Neuroscience Research Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan.
Neuroscience Research Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Biochimie. 2021 Dec;191:51-61. doi: 10.1016/j.biochi.2021.08.009. Epub 2021 Aug 27.
Methylphenidate (MPD), a psychostimulant, is a prescription medicine for treating attention deficit hyperactivity disorder (ADHD). Previously we have shown that moderate doses of MPD enhanced learning and memory while higher doses impaired it. To understand neurochemical mechanisms and receptors involved in memory enhancing and impairing effects of MPD, the present study concerns the effects of these doses of MPD on serotonin, 5-HT1A, GABA, and NMDA receptor mRNA expression in the prefrontal cortex (PFC). We found that low doses (2.5 mg/kg) of MPD improved performance in the water-maze test but higher doses (5 mg/kg) impaired memory retention. Animals showing improved performance had high 5-HT metabolism in the PFC while these levels were not affected in the group treated with higher MPD doses and exhibiting impaired memory. There was downregulation of 5-HT1A receptors in the PFC of rats treated with higher dose MPD, which didn't occur in low dose of MPD treated animals. Further, a decrease in GABAreceptor mRNA expression occurred in low doses of MPD treated animals and GluN2A expression was reduced in higher doses of MPD treated animals. The findings suggest that memory enhancing doses of MPD increase 5-HT and reduce GABA receptor mRNA expression in the PFC to release excitatory glutamate neurons from the inhibitory influence of GABA. Conversely, higher dose of MPD downregulates 5-HT1A receptor mRNA expression to enhance inhibitory GABA influence on glutamate neurons and impair cognitive performance. The findings show an important role of 5-HT1A heteroreceptors in the PFC for improving therapeutic use of MPD and developing novel cognitive enhancers.
哌醋甲酯（MPD），一种精神兴奋剂，是一种治疗注意力缺陷多动障碍（ADHD）的处方药。此前我们已经表明，中等剂量的 MPD 增强了学习和记忆，而较高剂量则损害了它。为了了解参与 MPD 增强和损害记忆的神经化学机制和受体，本研究关注这些剂量的 MPD 对前额叶皮层（PFC）中 5-羟色胺、5-HT1A、GABA 和 NMDA 受体 mRNA 表达的影响。我们发现，低剂量（2.5mg/kg）的 MPD 改善了水迷宫测试中的表现，但高剂量（5mg/kg）损害了记忆保留。表现出改善的动物在 PFC 中具有高 5-HT 代谢，而在接受更高 MPD 剂量治疗且记忆受损的组中则没有受到影响。在接受更高剂量 MPD 治疗的大鼠的 PFC 中，5-HT1A 受体下调，而在接受低剂量 MPD 治疗的动物中则没有。此外，在低剂量 MPD 治疗的动物中，GABAA 受体 mRNA 表达减少，而在高剂量 MPD 治疗的动物中，GluN2A 表达减少。研究结果表明，记忆增强剂量的 MPD 增加 5-HT 并减少 PFC 中的 GABA 受体 mRNA 表达，从而使兴奋性谷氨酸神经元免受 GABA 的抑制影响。相反，更高剂量的 MPD 下调 5-HT1A 受体 mRNA 表达，以增强 GABA 对谷氨酸神经元的抑制作用并损害认知表现。研究结果表明，PFC 中的 5-HT1A 异受体在改善 MPD 的治疗用途和开发新型认知增强剂方面具有重要作用。
