Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Neuropsychopharmacology. 2017 Nov;42(12):2314-2324. doi: 10.1038/npp.2017.87. Epub 2017 May 2.


Smoking is the leading cause of preventable death in the United States and success rates for quitting remain low. High relapse rates are attributed to pervasive nicotine-reinforced associative learning of incentive cues that is highly resistant to extinction. Why such learning is so persistent is poorly understood but may arise as a consequence of neuroadaptations in synaptic plasticity induced by chronic nicotine. We used whole-cell patch clamp recording to investigate the effect of chronic nicotine (cNIC) on synaptic plasticity in dopamine D2 receptor-expressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited long-term potentiation in response to high-frequency stimulation instead of the expected depression. cNIC decreased baseline AMPA/NMDA ratio, arising from increased NMDA currents enriched in the NR2B subunit with a concomitant upregulation of NMDA-only, silent synapses. These data demonstrate that cNIC can increase silent synapses in MSNs, as observed with cocaine and opiates, and alter the regulation of corticostriatal plasticity. Prior work has characterized cocaine- and morphine-induced upregulation of silent synapses in the ventral striatum; we show it can occur in the dorsal striatum, a region associated with later stages of addiction, craving, and cue-induced relapse.

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Globus Pallidus / drug effects
  • Globus Pallidus / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Nicotine / administration & dosage*
  • Organ Culture Techniques
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synapses / drug effects
  • Synapses / physiology


  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Nicotine