Signaling pathway adaptations and novel protein kinase A substrates related to behavioral sensitization to cocaine

Amy C. Boudreau, Carrie R. Ferrario, Marc J. Glucksman, Marina Wolf

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Behavioral sensitization is an animal model for aspects of cocaine addiction. Cocaine-sensitized rats exhibit increased AMPA receptor (AMPAR) surface expression in the nucleus accumbens (NAc) which may in turn enhance drug seeking. To identify signaling pathways contributing to AMPAR up-regulation, we measured AMPAR surface expression and signaling pathway activation in the NAc of cocaine-sensitized rats, cocaine-exposed rats that failed to sensitize and saline controls on withdrawal days (WD) 1, 7, and 21. We focused on calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated protein kinase (ERK), and protein kinase A (PKA). In sensitized rats, AMPAR surface expression was elevated on WD7 and WD21 but not WD1. ERK2 activation followed a parallel time-course, suggesting a role in AMPAR up-regulation. Both sensitized and non-sensitized rats exhibited CaMKII activation on WD7, suggesting that CaMKII activation is not sufficient for AMPAR up-regulation. PKA phosphorylation, measured using an antibody recognizing phosphorylated PKA substrates, increased gradually over withdrawal in sensitized rats, from below control levels on WD1 to significantly greater than controls on WD21. Using proteomics, novel sensitization-related PKA substrates were identified, including two structural proteins (CRMP-2 and α-tubulin) that we speculate may link PKA signaling to previously reported dendritic remodeling in NAc neurons of cocaine-sensitized rats.

Original languageEnglish (US)
Pages (from-to)363-377
Number of pages15
JournalJournal of Neurochemistry
Volume110
Issue number1
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

Fingerprint

Cyclic AMP-Dependent Protein Kinases
AMPA Receptors
Cocaine
Rats
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Substrates
Nucleus Accumbens
Chemical activation
Up-Regulation
Cocaine-Related Disorders
Calcium-Calmodulin-Dependent Protein Kinases
Phosphorylation
Neuronal Plasticity
Level control
Extracellular Signal-Regulated MAP Kinases
Tubulin
Proteomics
Protein Kinases
Neurons
Animals

Keywords

  • Addiction
  • AMPA receptor
  • Cocaine
  • Nucleus accumbens
  • Rat
  • Receptor trafficking
  • Sensitization

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Signaling pathway adaptations and novel protein kinase A substrates related to behavioral sensitization to cocaine. / Boudreau, Amy C.; Ferrario, Carrie R.; Glucksman, Marc J.; Wolf, Marina.

In: Journal of Neurochemistry, Vol. 110, No. 1, 01.07.2009, p. 363-377.

Research output: Contribution to journalArticle

Boudreau, Amy C. ; Ferrario, Carrie R. ; Glucksman, Marc J. ; Wolf, Marina. / Signaling pathway adaptations and novel protein kinase A substrates related to behavioral sensitization to cocaine. In: Journal of Neurochemistry. 2009 ; Vol. 110, No. 1. pp. 363-377.
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