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表面N-甲基-D-天冬氨酸受体的稳定性控制对苯丙胺的突触和行为适应性。

Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.

作者信息

Mao Li-Min, Wang Wei, Chu Xiang-Ping, Zhang Guo-Chi, Liu Xian-Yu, Yang Yuan-Jian, Haines Michelle, Papasian Christopher J, Fibuch Eugene E, Buch Shilpa, Chen Jian-Guo, Wang John Q

机构信息

Department of Basic Medical Science, University of Missouri Kansas City, USA.

出版信息

Nat Neurosci. 2009 May;12(5):602-10. doi: 10.1038/nn.2300. Epub 2009 Apr 6.

DOI:10.1038/nn.2300
PMID:19349975
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2749993/
Abstract

Plastic changes in glutamatergic synapses that lead to endurance of drug craving and addiction are poorly understood. We examined the turnover and trafficking of NMDA receptors and found that chronic exposure to the psychostimulant amphetamine (AMPH) induced selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. This downregulation was a long-lived event and was a result of the destabilization of surface-expressed NR2B caused by accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translated to the modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induced and restoration of NR2B loss prevented behavioral sensitization to AMPH. Our data identify NR2B as an important regulator in the remodeling of excitatory synapses and persistent psychomotor plasticity in response to AMPH.

摘要

导致药物渴望和成瘾持续存在的谷氨酸能突触的可塑性变化目前仍知之甚少。我们研究了NMDA受体的更新和运输，发现长期暴露于精神兴奋剂苯丙胺（AMPH）会导致大鼠纹状体神经元突触部位受限的表面膜池中NMDA受体NR2B亚基的选择性下调。这种下调是一个长期事件，是由泛素-蛋白酶体系统加速泛素化和关键NR2B锚定蛋白降解导致表面表达的NR2B不稳定所致。突触NR2B的生化损失进一步转化为皮质-伏隔核谷氨酸能突触处长期抑制形式的突触可塑性调节。在行为上，NR2B的基因破坏诱导和NR2B损失的恢复可防止对AMPH的行为敏化。我们的数据确定NR2B是兴奋性突触重塑和对AMPH反应中持续精神运动可塑性的重要调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/88cc7345e820/nihms-103078-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/93d5f83a71fc/nihms-103078-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/022658cc1c9a/nihms-103078-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/3fde45bb4c3a/nihms-103078-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/88cc7345e820/nihms-103078-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/93d5f83a71fc/nihms-103078-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/022658cc1c9a/nihms-103078-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/3fde45bb4c3a/nihms-103078-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad77/2749993/88cc7345e820/nihms-103078-f0005.jpg

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