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The Journal of Neuroscience, November 26, 2008, 28(48):12808-12814; doi:10.1523/JNEUROSCI.2060-08.2008

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Brief Communications
Renewed Cocaine Exposure Produces Transient Alterations in Nucleus Accumbens AMPA Receptor-Mediated Behavior

Ryan K. Bachtell and David W. Self

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Dr. Ryan K. Bachtell at his present address: Department of Psychology and Center for Neuroscience, Campus Box 345, University of Colorado, Boulder, CO 80309-0345. Email: Ryan.Bachtell{at}Colorado.edu

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 cocaine-induced 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.

Key words: glutamate; neuroplasticity; dopamine; sensitization; psychostimulant; dopamine

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Received May 4, 2008; revised Oct. 8, 2008; accepted Oct. 17, 2008.

Correspondence should be addressed to Dr. Ryan K. Bachtell at his present address: Department of Psychology and Center for Neuroscience, Campus Box 345, University of Colorado, Boulder, CO 80309-0345. Email: Ryan.Bachtell{at}Colorado.edu

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