Endogenous dopamine and endocannabinoid signaling mediate cocaine-induced reversal of AMPAR synaptic potentiation in the nucleus accumbens shell

Anna E. Ingebretson, Matthew C. Hearing, Ethan D. Huffington, Mark J. Thomas

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within meso-corticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During a 10–14 day period of abstinence from cocaine, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, rapidly reverses and depotentiates enhanced AMPAR signaling. To understand how re-exposure to cocaine alters AMPAR synaptic transmission, we investigated the roles of dopamine and endocannabinoid (eCB) signaling in modifying synaptic strength in the NAc shell. Using patch-clamp recordings from NAc slices prepared after 10–14 days of abstinence from repeated cocaine, we found that AMPAR-mediated depotentiation is rapidly induced in the NAc shell within 20 min of cocaine re-exposure ex vivo, and persists for up to five days before synapses return to levels of potentiation observed during abstinence. In cocaine-treated animals, global dopamine receptor activation was both necessary and sufficient for the cocaine-evoked depotentiation of AMPAR synaptic function. Additionally, we identified that CB1 receptors are engaged by endogenous endocannabinoids (eCBs) during re-exposure to cocaine ex vivo. Overall, these results indicate the central role that dopamine and eCB signaling mechanisms play in modulating cocaine-induced AMPAR plasticity in the NAc shell.

Original languageEnglish (US)
Pages (from-to)154-165
Number of pages12
StatePublished - Mar 15 2018

Bibliographical note

Funding Information:
This work was supported by the National Institute on Drug Abuse to MJT ( R01DA019666 , K02 DA035459 ) and AEI ( T32 DA007234 ), the University of Minnesota Doctoral Dissertation Fellowship to AEI, University of Minnesota MnDRIVE Fellowship to MCH, and the Breyer-Longden Family Research Fund .

Publisher Copyright:
© 2017 Elsevier Ltd


  • AMPA receptor
  • Cocaine
  • Dopamine
  • Endocannabinoid
  • Nucleus accumbens
  • Synaptic plasticity


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