Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Behav Brain Res. 2012 Dec 1;235(2):287-92. doi: 10.1016/j.bbr.2012.08.016. Epub 2012 Aug 16.
Accumulated evidence indicates that metabotropic glutamate 5 (mGlu5) receptor blockade exerts antidepressant-like and anxiolytic-like effects in several animal models. The novelty-suppressed feeding (NSF) test is used to measure anxiety-induced hypophagia in rodents. Anxiogenic-like behavior can be counteracted by acute treatment with anxiolytics or chronic treatment with antidepressants. The objective of the present study was to investigate the effect of an mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), using the NSF test and to investigate the mechanisms underlying the effects of MPEP. The administration of MPEP at 1 h prior to testing significantly shortened the latency period until feed (an acute effect), and this effect lasted for 24 h (a sustained effect), similar to the results observed using the N-methyl-D-aspartate receptor antagonist ketamine. Pretreatment with a protein synthesis inhibitor, anisomycin, blocked the sustained, but not the acute, effects of MPEP, suggesting the involvement of new protein synthesis in the sustained effect of MPEP. In addition, the sustained effect of MPEP in the NSF test was partially abolished by pretreatment with a mammalian target of rapamycin (mTOR) antagonist, rapamycin. In contrast, a tropomyosin-related kinase, the tyrosine kinase inhibitor K252a, did not counteract the sustained effects of MPEP in this test. Taken together, these results are the first report to demonstrate that the blockade of the mGlu5 receptor exerted acute and sustained effects in the NSF test and that new protein synthesis may contribute to the sustained effects of MPEP, which may not mediate brain-derived neurotrophic factor-mTOR signaling.
累积的证据表明，代谢型谷氨酸 5（mGlu5）受体阻断在几种动物模型中具有抗抑郁和抗焦虑样作用。新颖性抑制进食（NSF）测试用于测量啮齿动物的焦虑诱导性摄食量减少。急性使用抗焦虑药或慢性使用抗抑郁药可对抗焦虑样行为。本研究的目的是使用 NSF 测试研究 mGlu5 受体拮抗剂 2-甲基-6-（苯乙炔基）-吡啶（MPEP）的作用，并研究 MPEP 作用的机制。在测试前 1 小时给予 MPEP 可显著缩短进食潜伏期（急性作用），这种作用可持续 24 小时（持续作用），与使用 N-甲基-D-天冬氨酸受体拮抗剂氯胺酮的结果相似。蛋白质合成抑制剂anisomycin 的预处理阻断了 MPEP 的持续作用，但不阻断其急性作用，表明新蛋白质合成参与了 MPEP 的持续作用。此外，mTOR 拮抗剂 rapamycin 的预处理部分消除了 MPEP 在 NSF 测试中的持续作用。相比之下，原肌球蛋白相关激酶，酪氨酸激酶抑制剂 K252a，并没有在这个测试中对抗 MPEP 的持续作用。总之，这些结果首次表明，mGlu5 受体的阻断在 NSF 测试中具有急性和持续作用，新蛋白质合成可能有助于 MPEP 的持续作用，而这种作用可能不介导脑源性神经营养因子-mTOR 信号通路。
