Renewed cocaine exposure produces transient alterations in nucleus accumbens AMPA receptor-mediated behavior

Ryan K. Bachtell, David W. Self

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Withdrawal from repeated cocaine is associated with increased synaptic and extrasynaptic AMPA receptor (AMPAR) expression in nucleus accumbens (NAc) neurons and enhanced behavioral sensitivity to AMPAR stimulation. Recent studies found that increased membrane expression of AMPARs is reversed or normalized on cocaine reexposure in withdrawal, but the mechanism for this AMPAR plasticity and the behavioral implications are unknown. Here, we examine the effects of renewed cocaine exposure during withdrawal on enhanced NAc AMPAR sensitivity and investigate the underlying mechanisms. Cocaine reexposure transiently reversed enhanced NAc AMPAR-mediated locomotion 1 d later, while enhancing cocaine-induced locomotion. Reversal in AMPAR sensitivity was prohibited by NAc AMPAR blockade with CNQX during cocaine reexposure and mimicked by intra-NAc infusions of AMPA, suggesting that cocaineinduced glutamate stimulation of NAc AMPARs is necessary for reversing AMPAR responsiveness. Similarly, systemic treatment with the dopamine D1-like agonist SKF 81297 [(±)-6-chloro-7,8- dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] reversed AMPAR responsiveness in cocaine withdrawal, but the effect was prevented by local NAc AMPAR blockade in the NAc, and not local D1-like receptor blockade, suggesting a role for glutamate afferents in the reversal of enhanced AMPAR sensitivity. Together, these findings suggest that cocaine-induced glutamate release in sensitized animals is responsible for dynamic alterations in AMPAR function that contribute to enhanced cocaine sensitivity.

Original languageEnglish (US)
Pages (from-to)12808-12814
Number of pages7
JournalJournal of Neuroscience
Issue number48
StatePublished - Nov 26 2008


  • Dopamine
  • Glutamate
  • Neuroplasticity
  • Psychostimulant
  • Sensitization

ASJC Scopus subject areas

  • Neuroscience(all)


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