Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections

Neuron. 2014 Sep 17;83(6):1453-67. doi: 10.1016/j.neuron.2014.08.023. Epub 2014 Sep 4.


Glutamatergic projections from the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) contribute to cocaine relapse. Here we show that silent synapse-based remodeling of the two major mPFC-to-NAc projections differentially regulated the progressive increase in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Specifically, cocaine self-administration in rats generated AMPA receptor-silent glutamatergic synapses within both infralimbic (IL) and prelimbic mPFC (PrL) to NAc projections, measured after 1 day of withdrawal. After 45 days of withdrawal, IL-to-NAc silent synapses became unsilenced/matured by recruiting calcium-permeable (CP) AMPARs, whereas PrL-to-NAc silent synapses matured by recruiting non-CP-AMPARs, resulting in differential remodeling of these projections. Optogenetic reversal of silent synapse-based remodeling of IL-to-NAc and PrL-to-NAc projections potentiated and inhibited, respectively, incubation of cocaine craving on withdrawal day 45. Thus, pro- and antirelapse circuitry remodeling is induced in parallel after cocaine self-administration. These results may provide substrates for utilizing endogenous antirelapse mechanisms to reduce cocaine relapse.

Publication types

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

MeSH terms

  • Animals
  • Cocaine-Related Disorders / physiopathology*
  • Craving / physiology*
  • Drug-Seeking Behavior / physiology
  • Electrophysiology
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / physiopathology
  • Neuronal Plasticity / physiology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiopathology*
  • Optogenetics
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / drug effects
  • Synapses / physiology*