Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion.
Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion.
复制标题
DOI：
10.1016/j.biopsych.2015.04.019
复制
发表时间：
2016-06-01
影响因子：
10.6
通讯作者：
Law PY
中科院分区：
文献类型：
--
作者：
Kibaly C;Kam AY;Loh HH;Law PY
阿片类拮抗剂纳洛酮/纳洛酮参与改善学习和记忆，但其细胞和分子机制尚不清楚。我们研究了纳洛酮/纳洛酮对海马AMPAR运输（学习和记忆的分子底物）的影响，作为拮抗剂活性的可能机制。为了测量纳洛酮/纳洛酮调节的AMPAR运输，对原代海马神经元进行pHluorin-GluA 1成像和生化分析。为了确定GluA 1-S845磷酸化对由纳曲酮抑制内源性μ-阿片受体（莫尔）诱导的行为效应的体内作用，在长期施用纳曲酮后在水迷宫中测试莫尔敲除（MORKO）和GluA 1-S845 A突变体（其中Ser 845突变为Ala）小鼠。采用Western blot分析比较野生型和GluA 1-S845 A突变小鼠的行为反应和海马突触后密度（PSD）中GluA 1水平。在体外长期纳洛酮/纳洛酮暴露显着增加突触和突触外GluA 1膜表达以及GluA 1-S845磷酸化。在MORKO和GluA 1-S845 A突变小鼠中，纳曲酮没有改善学习，这表明纳曲酮通过抑制内源性莫尔作用和改变GluA 1磷酸化而起作用。纳洛酮治疗的野生型小鼠在获得的第三天海马PSD中磷酸化GluA 1-S845和GluA 1水平显著增加，这是纳洛酮显著改善学习的时间。在正常条件下，纳洛酮对空间学习和记忆的有益作用似乎是增加GluA 1-S845磷酸化依赖的AMPAR运输的结果。这些结果可以在记忆丧失的小鼠模型中进一步探索。
The opioid antagonists, naloxone/naltrexone, are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal AMPAR trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity. To measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-GluA1 imaging and biochemical analyses were performed on primary hippocampal neurons. To establish the in vivo role of GluA1-S845 phosphorylation on the behavioral effect induced by inhibition of the endogenous μ-opioid receptor (MOR) by naltrexone, MOR knockout (MORKO) and GluA1-S845A mutant (in which Ser845 was mutated to Ala) mice were tested in a water maze after chronic naltrexone administration. Behavioral responses and GluA1 levels in the hippocampal postsynaptic density (PSD) in wild-type and GluA1-S845A mutants mice were compared using Western blot analysis. In vitro prolonged naloxone/naltrexone exposure significantly increased synaptic and extrasynaptic GluA1 membrane expression as well as GluA1-S845 phosphorylation. In the MORKO and GluA1-S845A mutant mice, naltrexone did not improve learning, which suggests that naltrexone acts via inhibition of endogenous MOR action and alteration of GluA1 phosphorylation. Naltrexone-treated wild-type mice had significantly increased phosphorylated GluA1-S845 and GluA1 levels in their hippocampal PSD on the third day of acquisition, which is the time when naltrexone significantly improved learning. The beneficial effect of naltrexone on spatial learning and memory under normal conditions appears to be the result of increasing GluA1-S845 phosphorylation-dependent AMPAR trafficking. These results can be further explored in a mouse model of memory loss.