An allosteric modulator of metabotropic glutamate receptors (mGluR₂), (+)-TFMPIP, inhibits restraint stress-induced phasic glutamate release in rat prefrontal cortex.
An allosteric modulator of metabotropic glutamate receptors (mGluR₂), (+)-TFMPIP, inhibits restraint stress-induced phasic glutamate release in rat prefrontal cortex.
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DOI：
10.1111/j.1471-4159.2012.07784.x
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发表时间：
2012-08
影响因子：
4.7
通讯作者：
Gerhardt GA
中科院分区：
文献类型：
--
作者：
Hascup ER;Hascup KN;Pomerleau F;Huettl P;Hajos-Korcsok E;Kehr J;Gerhardt GA
一种新的正变构调节剂（PAM）的代谢型谷氨酸受体亚组2（mGluR 2）的潜在抗焦虑作用进行了研究，使用自参考记录技术与酶为基础的微电极阵列（MEA），可靠地测量紧张性和阶段性变化的细胞外谷氨酸水平清醒大鼠。研究涉及在皮下注射以下物质期间大鼠前额皮质中的谷氨酸测量：载体、mGluR 2/3激动剂、LY 354740（10 mg/kg）或mGluR 2 PAM，1-甲基-2-（（顺式-（R，R）-3-甲基-4-（4-三氟甲氧基-2-氟）苯基）哌啶-1-基）甲基）-1H-咪唑并[4，5-B]吡啶（（+）-TFMPIP; 1.0或17.8 mg/kg）。研究评估了紧张性谷氨酸水平的变化和对五分钟束缚应激的谷氨酸能反应。以1.0 mg/kg的剂量皮下注射（+）-TFMPIP（第3天：-7.1 ± 15.1净AUC;第5天：-24.8 ± 24.9净AUC）和17.8 mg/kg（第3天：-46.5 ± 33.0净AUC;第5天：34.6 ± 36.8净AUC）与溶剂对照组相比，显著减弱了应激诱发的谷氨酸释放（第3天：134.7 ± 50.6净AUC;第5天：286.6 ± 104.5净AUC），而mGluR 2/3激动剂LY 354740没有作用。这些化合物都没有显著影响静息谷氨酸水平，我们最近发现谷氨酸水平广泛来源于神经元。总之，这些数据支持全身施用（+）-TFMPIP产生谷氨酸的阶段性而非紧张性释放，其可能在应激对前额叶皮层中谷氨酸神经元系统的影响中起主要作用。
The potential anxiolytic effects of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor subgroup 2 (mGluR2) were investigated using a self-referencing recording technique with enzyme-based microelectrode arrays (MEAs) that reliably measures tonic and phasic changes in extracellular glutamate levels in awake rats. Studies involved glutamate measures in the rat prefrontal cortex during subcutaneous injections of the following: vehicle, a mGluR2/3 agonist, LY354740 (10 mg/kg), or a mGluR2 PAM, 1-Methyl-2-((cis-(R,R)-3-methyl-4-(4-trifluoromethoxy-2-fluoro)phenyl)piperidin-1-yl)methyl)-1H-imidazo[4,5-b]pyridine ((+)-TFMPIP; 1.0 or 17.8 mg/kg). Studies assessed changes in tonic glutamate levels and the glutamatergic responses to a five minute restraint stress. Subcutaneous injection of (+)-TFMPIP at a dose of 1.0 mg/kg (day 3: −7.1 ± 15.1 net AUC; day 5: −24.8 ± 24.9 net AUC) and 17.8 mg/kg (day 3: −46.5 ± 33.0 net AUC; day 5: 34.6 ± 36.8 net AUC) significantly attenuated the stress-evoked glutamate release compared to vehicle controls (day 3: 134.7 ± 50.6 net AUC; day 5: 286.6 ± 104.5 net AUC), while the mGluR2/3 agonist LY354740 had no effect. None of the compounds significantly affected resting glutamate levels, which we have recently shown to be extensively derived from neurons. Taken together, these data support that systemic administration of (+)-TFMPIP produces phasic rather than tonic release of glutamate that may play a major role in the effects of stress on glutamate neuronal systems in the prefrontal cortex.
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