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The Journal of Neuroscience, October 22, 2008, 28(43):11061-11070; doi:10.1523/JNEUROSCI.1221-08.2008

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Behavioral/Systems/Cognitive
Phosphorylation-Dependent Trafficking of GluR2-Containing AMPA Receptors in the Nucleus Accumbens Plays a Critical Role in the Reinstatement of Cocaine Seeking

Katie R. Famous,¹ Vidhya Kumaresan,¹ Ghazaleh Sadri-Vakili,³ Heath D. Schmidt,¹ Dale F. Mierke,⁴ Jang-Ho J. Cha,³ and R. Christopher Pierce^1,2

Departments of ¹Pharmacology and ²Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, ³Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and ⁴Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755

Correspondence should be addressed to R. Christopher Pierce at his present address: Department of Psychiatry, University of Pennsylvania School of Medicine, 125 South 31st Street, Philadelphia, PA 19104. Email: rcpierce{at}mail.med.upenn.edu

A growing body of evidence indicates that enhanced AMPA-mediated glutamate transmission in the core of the nucleus accumbens is critically involved in cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. However, the extent to which increased glutamate transmission in the other major subregion of the nucleus accumbens, the shell, contributes to the reinstatement of cocaine seeking remains unclear. In the present experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.03, or 0.3 µg) into either the core or the shell of the nucleus accumbens before a systemic cocaine priming injection (10 mg/kg, i.p.) dose-dependently attenuated the reinstatement of drug seeking. Cocaine priming-induced reinstatement of cocaine seeking also was associated with increases in GluR2-pSer880 in the nucleus accumbens shell. The phosphorylation of GluR2 by PKC at Ser880 plays an important role in the trafficking of GluR2-containing AMPA receptors from the plasma membrane. The current results showed that administration of a cell-permeable peptide that disrupts GluR2 trafficking (Pep2-EVKI) into either the accumbens core or shell attenuated cocaine-induced reinstatement of drug seeking. Together, these findings indicate that changes in AMPA receptor-mediated glutamate transmission in both the nucleus accumbens core and shell are necessary for the reinstatement of drug seeking induced by a priming injection of cocaine. The present results also demonstrate that the reinstatement of cocaine seeking is associated with increases in the phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens.

Key words: relapse; addiction; psychostimulant; glutamate; CNQX; Pep2-EVKI

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Received March 20, 2008; revised Sept. 17, 2008; accepted Sept. 19, 2008.

Correspondence should be addressed to R. Christopher Pierce at his present address: Department of Psychiatry, University of Pennsylvania School of Medicine, 125 South 31st Street, Philadelphia, PA 19104. Email: rcpierce{at}mail.med.upenn.edu

This article has been cited by other articles:

				K. Bakshi, S. Gennaro, C. Y. Chan, M. Kosciuk, J. Liu, A. Stucky, E. Trenkner, E. Friedman, R. G. Nagele, and H.-Y. Wang Prenatal Cocaine Reduces AMPA Receptor Synaptic Expression through Hyperphosphorylation of the Synaptic Anchoring Protein GRIP J. Neurosci., May 13, 2009; 29(19): 6308 - 6319. [Abstract] [Full Text] [PDF]

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