Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression
Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression
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DOI：
10.1016/j.bbr.2012.10.023
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发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Chaki, Shigeyuki
中科院分区：
文献类型：
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作者：
Koike, Hiroyuki;Fukumoto, Kenichi;Chaki, Shigeyuki
我们先前发现，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体和哺乳动物雷帕霉素信号靶点的激活有助于第二组代谢性谷氨酸(mGlu2/3)受体拮抗剂的抗抑郁药样作用，提示该信号通路可能类似于氯胺酮抗抑郁药样作用的分子机制，氯胺酮是一种非竞争性N-甲基-D-天冬氨酸受体拮抗剂，在抑郁症患者中发挥快速而持续的抗抑郁作用。尽管脑源性神经营养因子(BDNF)/原肌球蛋白相关激酶B(TrkB)信号转导通路参与了氯胺酮的抗抑郁药样作用，但BDNF/TrkB信号转导通路参与mGlu2/3受体拮抗剂的作用尚未得到研究。因此，我们研究了mGlu2/3受体拮抗剂LY341495在诸如尾部悬吊试验(TST)和新奇抑制摄食试验(NSFT)等抑郁动物模型中是否需要激活BDNF/TrkB信号来发挥抗抑郁药样作用。当使用TST和NSFT评估时，在试验前30分钟给予LY341495可产生持续至少24小时的抗抑郁药样效应(急性效应)(持续效应)。TrkB酪氨酸激酶抑制剂K252a可阻断LY341495的持续作用，但不能阻断其急性作用。这些结果表明，BDNF/TrkB信号可能参与了LY341495的持续抗抑郁药样作用，正如氯胺酮治疗所观察到的那样。(C)2012爱思唯尔B.V.保留所有权利。
We previously revealed that the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor and mammalian target of rapamycin signaling contributed to the antidepressant-like effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists, suggesting that the signaling pathway may be similar to the molecular mechanisms underlying the antidepressant-like action of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that exertes rapid and sustained antidepressant effects in patients with depressive disorder. Although brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling reportedly participates in the antidepressant-like effects of ketamine, the involvement of BDNF/TrkB signaling in the action of mGlu2/3 receptor antagonists has not been investigated. We therefore examined whether the activation of BDNF/TrkB signaling is required for the antidepressant-like effects of LY341495, an mGlu2/3 receptor antagonist, in animal models of depression such as the tail suspension test (TST) and the novelty-suppressed feeding test (NSFT). The administration of LY341495 at 30 min prior to the test exerted antidepressant-like effects (acute effects) lasting for at least 24 h (sustained effects) when evaluated using the TST and NSFT. Pretreatment with K252a, a TrkB tyrosine kinase inhibitor, blocked the sustained, but not the acute, effects of LY341495. These results suggest that BDNF/TrkB signaling may be involved in the sustained antidepressant-like effects of LY341495, as observed for ketamine treatment. (c) 2012 Elsevier B.V. All rights reserved.