Cocaine and amphetamine induce overlapping but distinct patterns of AMPAR plasticity in nucleus accumbens medium spiny neurons

Jakub Jedynak, Matthew Hearing, Anna Ingebretson, Stephanie R. Ebner, Matthew Kelly, Rachel A. Fischer, Saïd Kourrich, Mark J. Thomas

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Repeated exposure to psychostimulant drugs such as cocaine or amphetamine can promote drug-seeking and -taking behavior. In rodent addiction models, persistent changes in excitatory glutamatergic neurotransmission in the nucleus accumbens (NAc) appear to drive this drug-induced behavioral plasticity. To study whether changes in glutamatergic signaling are shared between or exclusive to specific psychostimulant drugs, we examined synaptic transmission from mice following repeated amphetamine or cocaine administration. Synaptic transmission mediated by AMPA-type glutamate receptors was potentiated in the NAc shell 10-14 days following repeated amphetamine or cocaine treatment. This synaptic enhancement was depotentiated by re-exposure to amphetamine or cocaine. By contrast, in the NAc core only repeated cocaine exposure enhanced synaptic transmission, which was subsequently depotentiated by an additional cocaine but not amphetamine injection during drug abstinence. To better understand the drug-induced depotentiation, we replicated these in vivo findings using an ex vivo model termed 'challenge in the bath,' and showed that drug-induced decreases in synaptic strength occur rapidly (within 30 min) and require activation of metabotropic glutamate receptor 5 (mGluR5) and protein synthesis in the NAc shell, but not NAc core. Overall, these data demonstrate the specificity of neuronal circuit changes induced by amphetamine, introduce a novel method for studying drug challenge-induced plasticity, and define NAc shell medium spiny neurons as a primary site of persistent AMPA-type glutamate receptor plasticity by two widely used psychostimulant drugs.

Original languageEnglish (US)
Pages (from-to)464-476
Number of pages13
Issue number2
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
This work was supported by funding from the University of Minnesota Foundation, the Breyer-Longden Family Research Fund, and the National Institute on Drug Abuse to MJT (R01 DA019666, K02 DA035459) and to JJ, MK, AI, and SRE (T32 DA007234). The authors declare no conflict of interest.


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