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Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse
Shen, Hao-wei1; Scofield, Michael D.2; Boger, Heather2; Hensley, Megan2; Kalivas, Peter W.2
关键词Extrasynaptic Glutamate Receptor Glutamate Spillover Glutamate Uptake Heroin Self-administration Nucleus Accumbens Relapse
刊名JOURNAL OF NEUROSCIENCE
2014-04-16
DOI10.1523/JNEUROSCI.4564-13.2014
34期:16页:5649-5657
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Neurosciences
研究领域[WOS]Neurosciences & Neurology
关键词[WOS]CUE-INDUCED REINSTATEMENT ; COCAINE-SEEKING BEHAVIOR ; MGLUR5 ANTAGONIST MPEP ; NUCLEUS-ACCUMBENS CORE ; LONG-TERM POTENTIATION ; BASOLATERAL AMYGDALA ; NMDA RECEPTOR ; RAT-BRAIN ; TRANSPORTER EXPRESSION ; N-ACETYLCYSTEINE
英文摘要

Reducing the enduring vulnerability to relapse is a therapeutic goal in treating drug addiction. Studies with animal models of drug addiction show a marked increase in extrasynaptic glutamate in the core subcompartment of the nucleus accumbens (NAcore) during reinstated drug seeking. However, the synaptic mechanisms linking drug-induced changes in extrasynaptic glutamate to relapse are poorly understood. Here, we discovered impaired glutamate elimination in rats extinguished from heroin self-administration that leads to spillover of synaptically released glutamate into the nonsynaptic extracellular space in NAcore and investigated whether restoration of glutamate transport prevented reinstated heroin seeking. Through multiple functional assays of glutamate uptake and analyzing NMDA receptor-mediated currents, we show that heroin self-administration produced long-lasting downregulation of glutamate uptake and surface expression of the transporter GLT-1. This downregulation was associated with spillover of synaptic glutamate to extrasynaptic NMDA receptors within the NAcore. Ceftriaxone restored glutamate uptake and prevented synaptic glutamate spillover and cue-induced heroin seeking. Ceftriaxone-induced inhibition of reinstated heroin seeking was blocked by morpholino-antisense targeting GLT-1 synthesis. These data reveal that the synaptic glutamate spillover in the NAcore results from reduced glutamate transport and is a critical pathophysiological mechanism underling reinstated drug seeking in rats extinguished from heroin self-administration.

语种英语
WOS记录号WOS:000334926000026
项目编号DA003906 ; DA012513 ; DA015369 ; 81271472 ; 81221002
资助机构National Institutes of Health ; Natural Science Foundation of China
引用统计
被引频次:46[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57101
专题中国药物依赖性研究所
作者单位1.Peking Univ, Natl Inst Drug Dependence, Beijing 100191, Peoples R China
2.Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA
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Shen, Hao-wei,Scofield, Michael D.,Boger, Heather,et al. Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse[J]. JOURNAL OF NEUROSCIENCE,2014,34(16):5649-5657.
APA Shen, Hao-wei,Scofield, Michael D.,Boger, Heather,Hensley, Megan,&Kalivas, Peter W..(2014).Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse.JOURNAL OF NEUROSCIENCE,34(16),5649-5657.
MLA Shen, Hao-wei,et al."Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse".JOURNAL OF NEUROSCIENCE 34.16(2014):5649-5657.
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