Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving

Nat Neurosci. 2013 Nov;16(11):1644-51. doi: 10.1038/nn.3533. Epub 2013 Sep 29.


In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

Publication types

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

MeSH terms

  • Amygdala / cytology*
  • Amygdala / drug effects
  • Animals
  • Channelrhodopsins
  • Cocaine / adverse effects*
  • Conditioning, Operant
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / adverse effects*
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • GABA Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Male
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Nucleus Accumbens / cytology*
  • Nucleus Accumbens / drug effects
  • Picrotoxin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Self Administration
  • Spermine / pharmacology
  • Substance Withdrawal Syndrome* / pathology
  • Substance Withdrawal Syndrome* / physiopathology
  • Substance Withdrawal Syndrome* / psychology
  • Synapses / drug effects
  • Synapses / physiology*


  • Channelrhodopsins
  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Picrotoxin
  • Spermine
  • Cocaine