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

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

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)602-610
Number of pages9
JournalNature Neuroscience
Issue number5
StatePublished - May 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience


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