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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adaptation, Physiological / physiology
  • Adrenergic Uptake Inhibitors / pharmacology
  • Amphetamine / pharmacology*
  • Amphetamine-Related Disorders / metabolism
  • Amphetamine-Related Disorders / physiopathology*
  • Animals
  • Behavior / drug effects
  • Behavior / physiology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Male
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / physiology
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology


  • Adrenergic Uptake Inhibitors
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Amphetamine