title: 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.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave MSC 510, Charleston, SC 29425, USA.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Sun
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zelek-Molik
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: McGinty
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D058999:Drug-Seeking Behavior; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration; D013997:Time Factors
chemical_list: D003042:Cocaine; D017362:Cyclic AMP Response Element-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C489931:Ptpn5 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2