Reinstatement of nicotine seeking is mediated by glutamatergic plasticity

Proc Natl Acad Sci U S A. 2013 May 28;110(22):9124-9. doi: 10.1073/pnas.1220591110. Epub 2013 May 13.


Nicotine abuse and addiction is a major health liability. Nicotine, an active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, it is unknown whether, akin to illicit drugs of abuse such as cocaine or heroin, the adaptations endure and contribute to the propensity to relapse after discontinuing nicotine use. Using a rat model of cue-induced relapse, we made morphological and electrophysiological measures of synaptic plasticity, as well as quantified glutamate overflow, in the accumbens after 2 wk of withdrawal with extinction training. We found an enduring basal increase in dendritic spine head diameter and in the ratio of AMPA to NMDA currents in accumbens spiny neurons compared with yoked saline animals at 2 wk after the last nicotine self-administration session. This synaptic potentiation was associated with an increase in both AMPA (GluA1) and NMDA (GluN2A and GluN2B) receptor subunits, and a reduction in the glutamate transporter-1 (GLT-1). When nicotine seeking was reinstated by presentation of conditioned cues, there were parallel increases in behavioral responding, extracellular glutamate, and further increases in dendritic spine head diameter and ratio of AMPA to NMDA currents within 15 min. These findings suggest that targeting glutamate transmission might inhibit cue-induced nicotine seeking. In support of this hypothesis, we found that pharmacological inhibition of GluN2A with 3-Chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulfonamide (TCN-201) or GluN2B with ifenprodil abolished reinstated nicotine seeking. These results indicate that up-regulated GluN2A, GluN2B, and rapid synaptic potentiation in the accumbens contribute to cue-induced relapse to nicotine use.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cues
  • Dendritic Spines / physiology
  • Dendritic Spines / ultrastructure
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glutamates / metabolism*
  • Male
  • Microdialysis
  • Microscopy, Confocal
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recurrence
  • Self Administration
  • Synapses / drug effects*
  • Synapses / physiology
  • Time Factors
  • Tobacco Use Disorder / metabolism*


  • Excitatory Amino Acid Transporter 2
  • Glutamates
  • NR2B NMDA receptor
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Slc1a2 protein, rat
  • glutamate receptor ionotropic, AMPA 1
  • N-methyl D-aspartate receptor subtype 2A