The role of functional postsynaptic NMDA receptors in the central nucleus of the amygdala in opioid dependence.
The role of functional postsynaptic NMDA receptors in the central nucleus of the amygdala in opioid dependence.
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DOI：
10.1016/s0083-6729(10)82008-4
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发表时间：
2010
影响因子：
--
通讯作者：
Glass MJ
中科院分区：
文献类型：
--
作者：
Glass MJ
在边缘系统核，如中央杏仁核（CeA）的离子型N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的激活，在自主神经，行为和情感过程中发挥着重要作用，这些过程受到阿片类药物暴露的深刻影响。然而，NMDA受体的异质性超微结构分布，其复杂的药理学，以及遗传模型的缺乏阻碍了功能性杏仁核NMDA受体和阿片类药物依赖之间的联系的发展。为了克服这些缺点，高分辨率成像和分子药理学被用于：（1）鉴定CeA中必需NMDA-NR 1受体（NR 1）亚基的超微结构定位及其与μ阿片受体（μOR）的关系，μ OR是滥用阿片类药物（如吗啡）的主要细胞靶点;（2）确定CeA NR 1缺失对身体的影响，特别是，阿片类药物依赖的心理方面。结合免疫金和免疫过氧化物酶电子显微镜分析显示，NR 1在突触后（即，胞体，树突）位置的CeA神经元，在那里他们也经常与μOR共定位。通过局部显微注射表达绿色荧光蛋白（GFP）报告基因和Cre重组酶（rAAV-GFP-Cre）的亲神经性重组腺相关病毒（rAAV），在成年“floxed”NR 1（fNR 1）小鼠中，造成CeA神经元突触后部位NR 1的时空缺失。在CeA中缺失NR 1的小鼠在感觉、运动或伤害感受功能方面没有表现出明显的损害。此外，当给予慢性吗啡时，这些小鼠也表现出由纳洛酮引起的急性身体戒断综合征。然而，阿片类药物依赖的CeA NR 1基因敲除小鼠未能表现出条件性位置厌恶诱导纳洛酮沉淀撤退。这些结果表明，中央杏仁核神经元的突触后NMDA受体活性的表达与阿片类药物戒断相关的学习情感行为。阿片类药物依赖的生理和心理特性的神经遗传学分离证明了结合超微结构分析和分子药理学在阐明阿片类药物介导的可塑性的神经生物学机制方面的价值。
Activation of ionotropic N-methyl-D-aspartate (NMDA)-type glutamate receptors in limbic system nuclei, such as the central nucleus of the amygdala (CeA), plays an essential role in autonomic, behavioral, and affective processes that are profoundly impacted by exposure to opioids. However, the heterogeneous ultrastructural distribution of the NMDA receptor, its complex pharmacology, and the paucity of genetic models have hampered the development of linkages between functional amygdala NMDA receptors and opioid dependence. To overcome these shortcomings, high-resolution imaging and molecular pharmacology were used to (1) Identify the ultrastructural localization of the essential NMDA-NR1 receptor (NR1) subunit and its relationship to the mu-opioid receptor (μOR), the major cellular target of abused opioids like morphine, in the CeA and (2) Determine the effect of CeA NR1 deletion on the physical, and particularly, psychological aspects of opioid dependence. Combined immunogold and immuoperoxidase electron microscopic analysis showed that NR1 was prominently expressed in postsynaptic (i.e., somata, dendrites) locations of CeA neurons, where they were also frequently colocalized with the μOR. A spatial–temporal deletion of NR1 in postsynaptic sites of CeA neurons was produced by local microinjection of a neurotropic recombinant adeno-associated virus (rAAV), expressing the green fluorescent protein (GFP) reporter and Cre recombinase (rAAV–GFP–Cre), in adult “floxed” NR1 (fNR1) mice. Mice with deletion of NR1 in the CeA showed no obvious impairments in sensory, motor, or nociceptive function. In addition, when administered chronic morphine, these mice also displayed an acute physical withdrawal syndrome precipitated by naloxone. However, opioid-dependent CeA NR1 knockout mice failed to exhibit a conditioned place aversion induced by naloxone-precipitated withdrawal. These results indicate that postsynaptic NMDA receptor activity in central amygdala neurons is required for the expression of a learned affective behavior associated with opioid withdrawal. The neurogenetic dissociation of physical and psychological properties of opioid dependence demonstrates the value of combined ultrastructural analysis and molecular pharmacology in clarifying the neurobiological mechanisms subserving opioid-mediated plasticity.