Since we found that inhibition of cyclooxygenase-2 (COX-2) with concomitant application of a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist (MTEP) down-regulates mGluR7 in the hippocampus (HC) and changes behavior of mice, our team decided to investigate the mechanism responsible for the observed changes. The amino acid glutamate (Glu) is a major excitatory neurotransmitter in the brain. Glu uptake is regulated by excitatory amino acid transporters (EAAT). There are five transporters with documented expression in neurons and glia in the central nervous system (CNS). EAATs, maintain the correct transmission of the Glu signal and prevent its toxic accumulation by removing Glu from the synapse. It has been documented that the toxic level of Glu is one of the main causes of mental and cognitive abnormalities.

Given the above mechanisms involved in the functioning of the Glu synapse, we hypothesized modification of Glu uptake, involving EAATs as the cause of the observed changes. This study investigated the level of selected EAATs in the HC after chronic treatment with mGluR5 antagonist MTEP, NS398, and their combination using Western blot. Concomitant MTEP treatment with NS398 or a single administration of the above causes changes in LTP and modulation of EAAT levels in mouse HC. As EAATs are cellular markers of oxidative stress mechanisms, the E. coli lipopolysaccharide (LPS) challenge was performed. The modified Barnes maze test (MBM) revealed alterations in the mouse spatial learning abilities.

This study reports an interaction between the mGluR5 and COX-2 in the HC, with EAAT1 and EAAT3 involvement.

由于我们发现抑制 cyclooxygenase-2 (COX-2) 并同时应用代谢型谷氨酸受体亚型 5 (mGluR5) 拮抗剂 (MTEP) 会下调海马 (HC) 中的 mGluR7 并改变小鼠的行为，因此我们的团队决定调查导致观察到的变化的机制。氨基酸谷氨酸 (Glu) 是大脑中主要的兴奋性神经递质。Glu 摄取受兴奋性氨基酸转运蛋白 (EAAT) 的调节。在中枢神经系统 (CNS) 的神经元和神经胶质中有 5 种具有记录表达的转运蛋白。EAATs 通过从突触中去除 Glu 来维持 Glu 信号的正确传输并防止其毒性积累。据记载，Glu的毒性水平是导致精神和认知异常的主要原因之一。

鉴于上述涉及 Glu 突触功能的机制，我们假设 Glu 摄取的改变，涉及 EAAT 作为观察到的变化的原因。本研究调查了用 mGluR5 拮抗剂 MTEP、NS398 及其组合使用蛋白质印迹长期治疗后 HC 中选定 EAAT 的水平。与 NS398 或上述单次给药同时进行 MTEP 治疗会导致小鼠 HC 中 LTP 的变化和 EAAT 水平的调节。由于 EAAT 是氧化应激机制的细胞标志物，因此进行了大肠杆菌脂多糖 (LPS) 挑战。修改后的巴恩斯迷宫测试 (MBM) 揭示了小鼠空间学习能力的变化。

该研究报告了 HC 中 mGluR5 和 COX-2 之间的相互作用，EAAT1 和 EAAT3 参与其中。