Increased Insertion of Glutamate Receptor 2-Lacking α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptors at Hippocampal Synapses upon Repeated Morphine Administration
Increased Insertion of Glutamate Receptor 2-Lacking α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptors at Hippocampal Synapses upon Repeated Morphine Administration
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DOI：
10.1124/mol.109.060301
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发表时间：
2010-05-01
影响因子：
3.6
通讯作者：
Moron, Jose A.
中科院分区：
文献类型：
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作者：
Billa, Sophie K.;Liu, Jie;Moron, Jose A.
有证据表明，海马在重复药物治疗后的长期适应可能与其在记忆形成过程中的作用平行。有助于学习和记忆的神经可塑性也被认为是成瘾过程的基础。我们以前曾报道过，重复吗啡给药改变了海马突触内吞蛋白的局部分布，这反过来又会影响谷氨酸受体的表达。谷氨酸能系统，包括α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR），被认为参与阿片诱导的神经元和行为可塑性，虽然这些作用的机制才刚刚开始被理解。本研究进一步研究了吗啡重复给药对AMPAR表达和组成及其功能分支的影响。在最后一次吗啡注射后12小时，我们观察到海马突触组分中缺乏谷氨酸受体（GluR）2的AMPAR表达增加。免疫印迹研究表明，吗啡治疗后12小时，GluR 1亚基增加在突触后密度（PSD）和突触外的网站，而GluR 3亚基只增加在PSD，他们显示如何改变受体亚基的组成。此外，我们提供的电生理证据表明，AMPAR被切换到Ca 2+渗透（GluR 2缺乏）在突触重复吗啡治疗后12小时，影响海马神经元的长期抑郁症的程度。我们建议，吗啡诱导的海马神经元能突触传递的变化可能在重复吗啡给药诱导的神经适应中发挥重要作用。
Evidence suggests that the long-term adaptations in the hippocampus after repeated drug treatment may parallel its role during memory formation. The neuroplasticity that subserves learning and memory is also believed to underlie addictive processes. We have reported previously that repeated morphine administration alters local distribution of endocytic proteins at hippocampal synapses, which could in turn affect expression of glutamate receptors. Glutamatergic systems, including alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), are believed to be involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are only beginning to be understood. The present study further examines the effects of repeated morphine administration on the expression and composition of AMPARs and the functional ramifications. Twelve hours after the last morphine injection, we observed an increased expression of AMPARs lacking glutamate receptor (GluR) 2 in hippocampal synaptic fractions. Immunoblotting studies show that 12 h after morphine treatment, GluR1 subunits are increased at the postsynaptic density (PSD) and at extrasynaptic sites, whereas GluR3 subunits are only increased at the PSD, and they show how this alters receptor subunit composition. In addition, we provide electrophysiological evidence that AMPARs are switched to Ca2+-permeable (GluR2-lacking) at the synapse 12 h after repeated morphine treatment, affecting the magnitude of long-term depression at hippocampal neurons. We propose that morphine-induced changes in glutamatergic synaptic transmission in the hippocampus may play an important role in the neuroadaptations induced by repeated morphine administration.