Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal

  • Aric C. Madayag
  • Devan Gomez
  • Eden M. Anderson
  • Anna E. Ingebretson
  • Mark J. Thomas
  • Matthew C. HearingEmail author
Original Article


Despite evidence that morphine-related pathologies reflect adaptations in NAc glutamate signaling, substantial gaps in basic information remain. The current study examines the impact of non-contingent acute, repeated, and withdrawal-inducing morphine dosing regimens on glutamate transmission in D1- or D2-MSNs in the nucleus accumbens shell (NAcSh) and core (NAcC) sub-regions in hopes of identifying excitatory plasticity that may contribute to unique facets of opioid addiction-related behavior. Following an acute morphine injection (10 mg/kg), average miniature excitatory postsynaptic current (mEPSC) amplitude mediated by AMPA-type glutamate receptors was increased at D1-MSNs in the both the NAcShl and NAcC, whereas only the frequency of events was elevated at D2-MSNs in the NAcSh. In contrast, spontaneous somatic withdrawal induced by escalating dose of repeated morphine twice per day (20, 40, 60, 80, 100 mg/kg) enhanced mEPSC frequency specifically at D2-MSNs in the NAcSh. Similar to previous findings, excitatory drive was elevated at NAcSh D1-MSNs after 10–14 days home cage abstinence. Following abstinence, an acute drug re-exposure produced a rapid and enduring endocytosis of GluA2-containing AMPARs at D1-MSNs in the shell, that when blocked by an intra-NAc shell infusion of the Tat-GluA23Y peptide, increased reinstatement of morphine place preference—a phenomenon distinctly different than effects previously found with cocaine. The present study is the first to directly identify unique circuit specific adaptations in NAc glutamate synaptic transmission associated with morphine-related acute reward and somatic withdrawal as well as post-abstinence short-term plasticity. Moreover, while differing classes of abused drugs (i.e., psychostimulants and opioids) produce seemingly similar bidirectional plasticity in the NAc following drug re-exposure, our findings indicate this plasticity has distinct behavioral consequences.


Morphine Nucleus Accumben Medium Spiny Neurons Glutamate Plasticity AMPA Receptors Reinstatement Dopamine receptors 



The behavioral work is done in part with the support by the Mouse Behavior Core at the University of Minnesota, which received funding from the National Institute for Neurological Disorders and Stroke (P30 NS062158). These studies were also supported by funding from the National Institute on Drug Abuse Grant K99 DA038706 (to M.H.), R00DA038706 (M.H.), R00DA038706-04S1 (A.C.M), R01DA019666 (M.J.T.), K02DA035459 (M.J.T.) and T32 DA007234 (A.E.I.).


The following funding sources made the study possible: National Institute for Neurological Disorders and Stroke (P30 NS062158); National Institute on Drug Abuse Grant K99 DA038706 (to M.H.), R00DA038706 (M.H.), R00DA038706-04S1 (A.C.M), R01DA019666 (M.J.T.), K02DA035459 (M.J.T.) and T32 DA007234 (A.E.I.).

Complaince with ethical standards

Conflict of interest

The authors have no conflict of interest to disclose.

Ethical approval

The research in the current study used mice single or group housed on a 12-h light/dark cycle with food and water available ad libitum with experiments run during the light portion. All experiments were approved by the University of Minnesota and Marquette University Institutional Animal Care and Use Committee.

Informed consent

All authors have given their consent for manuscript submission.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical SciencesMarquette UniversityMilwaukeeUSA
  2. 2.Department of NeuroscienceUniversity of MinnesotaMinneapolisUSA

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