Extinction and Reinstatement of Cocaine-seeking in Self-administering Mice is Associated with Bidirectional AMPAR-mediated Plasticity in the Nucleus Accumbens Shell

Stephanie R. Ebner, Erin B. Larson, Matthew C. Hearing, Anna E. Ingebretson, Mark J. Thomas

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Experience-dependent synaptic plasticity is an important component of both learning and motivational disturbances found in addicted individuals. Here, we investigated the role of cocaine experience-dependent plasticity at excitatory synapses in the nucleus accumbens shell (NAcSh) in relapse-related behavior in mice with a history of volitional cocaine self-administration. Using an extinction/reinstatement paradigm of cocaine-seeking behavior, we demonstrate that cocaine-experienced mice with extinguished cocaine-seeking behavior show potentiation of synaptic strength at excitatory inputs onto NAcSh medium spiny neurons (MSNs). Conversely, we found that exposure to various distinct types of reinstating stimuli (cocaine, cocaine-associated cues, yohimbine “stress”) after extinction can produce a relative depotentiation of NAcSh synapses that is strongly associated with the magnitude of cocaine-seeking behavior exhibited in response to these challenges. Furthermore, we show that these effects are due to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-specific mechanisms that differ depending on the nature and context of the reinstatement-inducing stimuli. Together, our findings identify common themes as well as differential mechanisms that are likely important for the ability of diverse environmental stimuli to drive relapse to addictive-like cocaine-seeking behavior.

Original languageEnglish (US)
Pages (from-to)340-349
Number of pages10
StatePublished - Aug 1 2018

Bibliographical note

Funding Information:
SRE and EBL contributed equally to this work. SRE, EBL, and MJT designed experiments, SRE, EBL, MCH, and AEI conducted experiments, SRE and EBL analyzed data, and EBL and MJT wrote the manuscript. We would like to thank Dr. Manuel Esguerra and Dr. Michael Benneyworth for insightful comments and discussion related to this manuscript and Keelia Silvis, Ethan Huffington, and Johanna Back for technical assistance. This work was supported by funding from the National Institute on Drug Abuse grants R01 DA019666 , R21 DA033457 , K02 DA035459 (MJT) and T32 DA007234 (SRE and AEI), and by the University of Minnesota MnDRIVE Foundation (EBL and MCH). Behavioral experiments were run in the University of Minnesota Mouse Behavioral Core (supported by National Institutes of Health grant P30NS062158 ). The authors have no conflicts of interest related to this work.

Publisher Copyright:
© 2018


  • cocaine
  • nucleus accumbens
  • plasticity
  • relapse
  • self-administration


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