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首页> 外文期刊>Neuropsychopharmacology >The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-|[lsqb]|(2-methyl-1,3-thiazol-4-yl)ethynyl|[rsqb]|pyridine (MTEP) in Rodent Models of Anxiety
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The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-|[lsqb]|(2-methyl-1,3-thiazol-4-yl)ethynyl|[rsqb]|pyridine (MTEP) in Rodent Models of Anxiety

机译：有效和选择性mGlu5受体拮抗剂3- | [lsqb] |（2-甲基-1,3-噻唑-4-基）乙炔基| [rsqb] |吡啶（MTEP）在啮齿动物焦虑模型中的行为特征

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Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller–Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.
机译：先前的报道已经证明了强效且具有系统活性的代谢型谷氨酸亚型5（mGlu5）受体拮抗剂2-甲基-6-（苯基乙炔基）吡啶（MPEP）的抗焦虑作用。在这里，我们为新的mGlu5受体拮抗剂3-[（（2-甲基-1,3-噻唑-4-基）乙炔基]吡啶（MTEP）在大鼠中的抗焦虑活性提供证据，并将其与苯并二氮杂profile进行比较受体激动剂地西epa。 MTEP以剂量依赖的方式占据了mGlu5受体，在最高测试剂量（10 mg / kg，腹膜内）中基本上完全占据了受体。在适合于mGlu5受体介导的作用的剂量下，MTEP在改良的Geller-Seifter冲突模型中（与抗焦虑药类似）相一致，可显着减少恐惧增强的惊吓并增加惩罚反应。在两个模型中，抗焦虑药样反应的强度与地西epa相似。相反，当单独或与乙醇联合给药时，MTEP降低的未惩罚响应程度比地西epa小，并且对轮转性能没有影响。在该模型中用MTEP重复给药消除了急性给药中观察到的惩罚反应的增加。目前的结果表明，mGlu5受体拮抗剂缺乏苯二氮卓类药物所见的副作用，如镇静作用和乙醇相互作用，并提供了对mGlu5受体拮抗剂在调节情绪障碍中可能作用的见解。

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