Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.
Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.
复制标题
海马GLUA1的AMPA受体介导上下文依赖于吗啡的敏感性。
DOI：
10.1523/jneurosci.3835-11.2011
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发表时间：
2011-11-09
期刊：
影响因子：
--
通讯作者：
Morón JA
中科院分区：
文献类型：
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作者：
Xia Y;Portugal GS;Fakira AK;Melyan Z;Neve R;Lee HT;Russo SJ;Liu J;Morón JA
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）参与阿片类药物诱导的神经元和行为可塑性，尽管这些作用的机制尚不完全清楚。在本研究中，我们研究了重复吗啡给药对 AMPAR 表达、突触可塑性和吗啡情境依赖性行为敏感性的影响。我们发现吗啡治疗会导致海马体中突触 AMPAR 表达的变化，海马体是与学习和记忆密切相关的大脑区域。这些变化可以在治疗后一周观察到，但只有当小鼠对吗啡产生情境依赖性行为敏感性时才能观察到，其中吗啡治疗与给药环境相关。对吗啡的情境依赖性行为敏感性还与基础突触传递增加和海马长时程增强（LTP）破坏有关，而当吗啡给药与给药环境不配对时，这些效应就不那么强烈。有趣的是，一些影响可能与药物相关环境中吗啡暴露史有关，因为在停止吗啡治疗一周后接受盐水攻击的小鼠中观察到 AMPAR 表达、基础突触传递和 LTP 的改变。此外，我们证明了 GluA1 AMPAR 亚基的磷酸化在上下文依赖性行为敏化的获得和表达中起着至关重要的作用，因为这种行为被破坏 GluA1 磷酸化的病毒载体所阻断。这些数据提供了证据，表明海马体中的谷氨酸信号在吗啡的背景依赖性敏化中发挥重要作用，并支持进一步研究基于谷氨酸的治疗阿片成瘾的策略。
Glutamatergic systems, including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic AMPAR expression in the hippocampus, a brain area that is critically involved in learning and memory. These changes could be observed one week after the treatment, but only when mice developed context-dependent behavioral sensitization to morphine in which morphine treatment was associated with drug administration environment. Context-dependent behavioral sensitization to morphine was also associated with increased basal synaptic transmission and disrupted hippocampal long-term potentiation (LTP), whereas these effects were less robust when morphine administration was not paired with the drug administration environment. Interestingly, some effects may be related to the prior history of morphine exposure in the drug-associated environment, since alterations of AMPAR expression, basal synaptic transmission, and LTP were observed in mice that received a saline challenge one week after discontinuation of morphine treatment. Furthermore, we demonstrated that phosphorylation of GluA1 AMPAR subunit plays a critical role in the acquisition and expression of context-dependent behavioral sensitization, as this behavior is blocked by a viral vector that disrupts GluA1 phosphorylation. These data provide evidence that glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine and supports further investigation of glutamate-based strategies for treating opiate addiction.