title: Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation.
abstract: 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.
authors: Inserm, Unité Mixte de Recherche en Santé 952, F-75005 Paris, France.
authors: Antoine
authors: A
authors: Besnard
authors: Nicolas
authors: N
authors: Bouveyron
authors: Vincent
authors: V
authors: Kappes
authors: Vincent
authors: V
authors: Pascoli
authors: Christiane
authors: C
authors: Pagès
authors: Nicolas
authors: N
authors: Heck
authors: Peter
authors: P
authors: Vanhoutte
authors: Jocelyne
authors: J
authors: Caboche
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C494113:Elk1 protein, mouse; D010455:Peptides; D050807:ets-Domain Protein Elk-1; D003042:Cocaine