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The Journal of Neuroscience, September 26, 2007, 27(39):10621-10635; doi:10.1523/JNEUROSCI.2163-07.2007

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Behavioral/Systems/Cognitive
Cell Surface AMPA Receptors in the Rat Nucleus Accumbens Increase during Cocaine Withdrawal But Internalize after Cocaine Challenge in Association with Altered Activation of Mitogen-Activated Protein Kinases

Amy C. Boudreau, Jeremy M. Reimers, Michael Milovanovic, and Marina E. Wolf

Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095

Correspondence should be addressed to Marina E. Wolf, Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064-3095. Email: marina.wolf{at}rosalindfranklin.edu

Although some studies report increased responsiveness of nucleus accumbens (NAc) AMPA receptors (AMPARs) after withdrawal from repeated cocaine treatment, others report decreased responsiveness after withdrawal plus cocaine challenge. Here we examine this apparent contradiction by quantifying cell surface and intracellular AMPAR subunits in the NAc before and after a challenge injection in behaviorally sensitized rats. Because MAPKs (mitogen-activated protein kinases) regulate AMPAR trafficking and are implicated in addiction, we also evaluated phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Glutamate receptor 1 (GluR1) and GluR2 surface/intracellular (S/I) ratios were increased after 14 d of withdrawal in sensitized rats but were decreased 24 h after challenge with cocaine (which elicited a sensitized locomotor response) or saline (which elicited conditioned locomotion). These findings suggested redistribution of GluR1/2-containing receptors, a possibility supported by immunoprecipitation experiments indicating that most AMPARs in the NAc are GluR1/2 or GluR2/3, with few homomeric GluR1 or GluR1/3 receptors. In sensitized rats, ERK phosphorylation in the NAc increased during withdrawal and normalized after cocaine challenge. JNK phosphorylation also increased after withdrawal, but after cocaine challenge, it was inversely related to GluR1 and GluR2 S/I ratios. After saline challenge, p38 phosphorylation was increased. In summary, surface expression of GluR1/2-containing AMPARs increased in the NAc of sensitized rats, but AMPARs internalized after a single reexposure to cocaine or cocaine-related cues. ERK phosphorylation paralleled AMPAR surface expression. Although JNK results were complex, JNK and p38 may be involved in AMPAR internalization after cocaine or saline challenge, respectively.

Key words: addiction; AMPA receptor; cocaine; nucleus accumbens; rat; sensitization; trafficking

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Received May 10, 2007; revised Aug. 19, 2007; accepted Aug. 19, 2007.

Correspondence should be addressed to Marina E. Wolf, Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064-3095. Email: marina.wolf{at}rosalindfranklin.edu

Related articles in J. Neurosci.:

Cocaine Experience Guides Dynamic Changes in AMPA Receptors within the Nucleus Accumbens

Joshua L. Jones
J. Neurosci. 2008 28: 2967-2969. [Full Text]  

This article has been cited by other articles:

				X. Sun, M. Milovanovic, Y. Zhao, and M. E. Wolf Acute and Chronic Dopamine Receptor Stimulation Modulates AMPA Receptor Trafficking in Nucleus Accumbens Neurons Cocultured with Prefrontal Cortex Neurons J. Neurosci., April 16, 2008; 28(16): 4216 - 4230. [Abstract] [Full Text] [PDF]

				J. L. Jones Cocaine Experience Guides Dynamic Changes in AMPA Receptors within the Nucleus Accumbens J. Neurosci., March 19, 2008; 28(12): 2967 - 2969. [Full Text] [PDF]

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