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

Brian R. Lee, Yao Ying Ma, Yanhua H. Huang, Xiusong Wang, Mami Otaka, Masago Ishikawa, Peter A. Neumann, Nicholas M. Graziane, Travis E. Brown, Anna Suska, Changyong Guo, Mary Kay Lobo, Susan R. Sesack, Marina E. Wolf, Eric J. Nestler, Yavin Shaham, Oliver M. Schlüter, Yan Dong

Research output: Contribution to journalArticlepeer-review

236 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1644-1651
Number of pages8
JournalNature Neuroscience
Issue number11
StatePublished - Nov 2013

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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