Memantine attenuated alcohol withdrawal-induced anxiety-like behaviors through down-regulating NR1-CaMKII-ERK signaling pathway
Memantine attenuated alcohol withdrawal-induced anxiety-like behaviors through down-regulating NR1-CaMKII-ERK signaling pathway
复制标题
美金刚通过下调 NR1-CaMKII-ERK 信号通路减轻酒精戒断引起的焦虑样行为
DOI：
10.1016/j.neulet.2018.09.006
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发表时间：
2018-11-01
影响因子：
2.5
通讯作者：
Zhu Yongsheng，yongsheng
中科院分区：
文献类型：
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作者：
Ji Yuanyuan，Yuan Yuan;Zhu Junyan，Jun-Yan;Zhu Yongsheng，yongsheng
酗酒和焦虑症经常同时发生，但其潜在的细胞机制仍不清楚。N-甲基-D-天冬氨酸受体(NMDAR)最近受到了那些对焦虑的神经生物学感兴趣的人的关注。建立慢性酒精暴露大鼠模型(连续28天摄入20%酒精，戒断6 h)。在这里，我们通过系统注射美金刚(一种NMDAR抑制剂)，研究了NMDAR1(NR1)、钙/钙调素依赖的蛋白激酶II(CaMKII)和细胞外信号调节蛋白激酶(ERK)通路在暴露于开阔场地和高架+迷宫(EPM)的大鼠焦虑样行为调节中的作用。我们发现酒精戒断后，NR1-CaMKII-ERK信号通路在内侧前额叶皮质(MPFC)和伏核外壳(NAcSh)被激活，但不在核心(NACC)被激活。美金刚治疗显著改善了酒精戒断大鼠的焦虑样行为。此外，美金刚还能均匀抑制酒精戒断诱导的NR1-CaMKII-ERK通路的磷酸化。我们的结果表明，mPFC和NAcSh中NR1-CaMKII-ERK通路的激活是酒精戒断诱导焦虑行为的分子机制的重要贡献。因此，NMDAR信号通路抑制剂是治疗酒精滥用的潜在疗法。
Alcohol abuse and anxiety disorders often occur concurrently, but their underlying cellular mechanisms remain unclear. N-methyl-D-aspartic acid receptors (NMDARs) have recently received attention from those interested in the neurobiology of anxiety. A chronic alcohol exposure rat model (28 consecutive days of 20% alcohol intake and 6 h of withdrawal) was established. Here, we investigated the NMDAR1 (NR1), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERK) pathway in the modulation of anxiety-like behaviors in rats exposed to an open field and elevated plus maze (EPM) through systematic injections of memantine (a NMDAR inhibitor). We found that the NR1-CaMKII-ERK signaling pathway was activated after alcohol withdrawal in medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh) but not core (NAcC). Memantine treatment greatly ameliorated anxiety-like behavior in the rats experiencing alcohol withdrawal. Moreover, memantine uniformly suppressed the phosphorylation of NR1-CaMKII-ERK pathway induced by alcohol withdrawal. Our results suggest that activation of the NR1-CaMKII-ERK pathway in the mPFC and NAcSh is an important contributor to the molecular mechanisms underlying alcohol withdrawal-induced anxiety behaviors. NMDAR signaling pathway inhibitors are thus potential therapeutics for treating alcohol abuse.