AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

Andrew F. Scheyer, Jessica A. Loweth, Daniel T. Christian, Jamie Uejima, Rana Rabei, Tuan Le, Hubert Dolubizno, Michael T. Stefanik, Conor H. Murray, Courtney Sakas, Marina E. Wolf*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


Background The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)–mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. Methods Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra–NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test. Results Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra–NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration. Conclusions These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalBiological psychiatry
Issue number9
StatePublished - Nov 1 2016


  • Ca-permeable AMPA receptors
  • Extended-access drug self-administration
  • Incubation of craving
  • Metabotropic glutamate receptor 1 (mGluR1)
  • Methamphetamine
  • Nucleus accumbens

ASJC Scopus subject areas

  • Biological Psychiatry


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