Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation

J Neurosci. 2011 Oct 5;31(40):14296-307. doi: 10.1523/JNEUROSCI.2890-11.2011.


Activation of the extracellular signal-regulated kinase (ERK) signaling pathway in the striatum is crucial for molecular adaptations and long-term behavioral alterations induced by cocaine. In response to cocaine, ERK controls the phosphorylation levels of both mitogen and stress-activated protein kinase 1 (MSK-1), a nuclear kinase involved in histone H3 (Ser10) and cAMP response element binding protein phosphorylation, and Elk-1, a transcription factor involved in serum response element (SRE)-driven gene regulations. We recently characterized the phenotype of msk-1 knock-out mice in response to cocaine. Herein, we wanted to address the role of Elk-1 phosphorylation in cocaine-induced molecular, morphological, and behavioral responses. We used a cell-penetrating peptide, named TAT-DEF-Elk-1 (TDE), which corresponds to the DEF docking domain of Elk-1 toward ERK and inhibits Elk-1 phosphorylation induced by ERKs without modifying ERK or MSK-1 in vitro. The peptide was injected in vivo before cocaine administration in mice. Immunocytochemical, molecular, morphological, and behavioral studies were performed. The TDE inhibited Elk-1 and H3 (Ser10) phosphorylation induced by cocaine, sparing ERK and MSK-1 activation. Consequently, TDE altered cocaine-induced regulation of genes bearing SRE site(s) in their promoters, including c-fos, zif268, ΔFosB, and arc/arg3.1 (activity-regulated cytoskeleton-associated protein). In a chronic cocaine administration paradigm, TDE reversed cocaine-induced increase in dendritic spine density. Finally, the TDE delayed the establishment of cocaine-induced psychomotor sensitization and conditioned-place preference. We conclude that Elk-1 phosphorylation downstream from ERK is a key molecular event involved in long-term neuronal and behavioral adaptations to cocaine.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Cocaine / pharmacology*
  • Dose-Response Relationship, Drug
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Peptides / metabolism
  • Peptides / pharmacology
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • ets-Domain Protein Elk-1 / antagonists & inhibitors*
  • ets-Domain Protein Elk-1 / metabolism*


  • Elk1 protein, mouse
  • Peptides
  • ets-Domain Protein Elk-1
  • Cocaine