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 GABA_Areceptor 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_A 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) 是一种精神兴奋剂，是一种治疗注意力缺陷多动障碍 (ADHD) 的处方药。以前我们已经证明，中等剂量的 MPD 可以增强学习和记忆力，而高剂量会损害它。为了了解参与 MPD 记忆增强和损害作用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) 中血清素、5-HT1A、GABA 和 NMDA 受体 mRNA 表达的影响。我们发现低剂量 (2.5 mg/kg) 的 MPD 改善了水迷宫测试中的表现，但高剂量 (5 mg/kg) 损害了记忆力。表现出改善的动物在 PFC 中具有较高的 5-HT 代谢，而这些水平在接受较高 MPD 剂量治疗并表现出记忆受损的组中不受影响。高剂量 MPD 治疗大鼠 PFC 中 5-HT1A 受体下调，而低剂量 MPD 治疗动物没有这种情况。此外，GABA 减少_{在低剂量的 MPD 治疗动物中出现}受体 mRNA 表达，而在更高剂量的 MPD 治疗动物中 GluN2A 表达降低。研究结果表明，增强记忆力的 MPD 剂量会增加 5-HT 并降低 PFC 中 GABA _A受体 mRNA 的表达，从而从 GABA 的抑制作用中释放兴奋性谷氨酸神经元。相反，较高剂量的 MPD 下调 5-HT1A 受体 mRNA 表达以增强抑制性 GABA 对谷氨酸神经元的影响并损害认知能力。研究结果表明 5-HT1A 异源受体在 PFC 中对改善 MPD 的治疗用途和开发新的认知增强剂具有重要作用。