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Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex

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An Erratum to this article was published on 05 June 2013

Abstract

Rationale

Dephosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) in the dorsomedial prefrontal cortex (dmPFC) at the end of short access (ShA) cocaine self-administration is implicated in cocaine seeking. However, what receptors and phosphatases mediate this effect and whether ERK/CREB and related phospho-proteins in the dmPFC react similarly during early withdrawal from long access (LgA) cocaine self-administration are unknown.

Objectives

The effects of ShA vs. LgA cocaine self-administration on the phosphorylation of protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phosphatase (STEP), as well as GluN and GluA receptor subtype expression in the dmPFC during early withdrawal, were compared.

Methods

Rats self-administered cocaine or received saline during 2- or 6-h daily sessions for 10–11 days. Two hours after the final session, the dmPFC was dissected out and processed for immunoblotting.

Results

Similar to previous findings after ShA cocaine, phospho-ERK and phospho-CREB in the dmPFC were decreased after LgA cocaine. Cocaine elevated phospho-PP2A (deactivation) and decreased phospho-STEP (activation) in both ShA and LgA cocaine rats. GluN1, GluN2B, and phospho-GluN2B Tyr1472 in the dmPFC were decreased after ShA and LgA cocaine. Further, a significant reduction of GluA2, GluA1, and phospho-GluA1 Ser845 was found only in LgA rats.

Conclusions

Activation of phospho-STEP may underlie ERK and CREB dephosphorylation in the dmPFC as well as internalization and degradation of GluN complexes during early withdrawal from both ShA and LgA cocaine self-administration, whereas differential alteration of AMPA receptor subunits after ShA and LgA cocaine self-administration depends on cocaine intake.

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Acknowledgments

The authors thank Phong Do, Andrew Nowak, and John Yang for excellent technical assistance and Dr. Paul Lombroso for the phospho-STEP antiserum. This research was supported by P50 DA015369 and RO1 DA033479.

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The authors have no conflicts of interest.

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  1. Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave MSC 510, Charleston, SC 29425, USA

    Wei-Lun Sun, Agnieszka Zelek-Molik & Jacqueline F. McGinty

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Correspondence to Jacqueline F. McGinty.

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Sun, WL., Zelek-Molik, A. & McGinty, J.F. Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. Psychopharmacology 229, 603–613 (2013). https://doi.org/10.1007/s00213-013-3118-5

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