Parsing Molecular and Behavioral Effects of Cocaine in Mitogen- and Stress-Activated Protein Kinase-1-Deficient Mice

• DOI: 10.1523/jneurosci.1711-05.2005
• Publication Date: 2005-12-07T18:02:49Z
• Authors: Karen Brami-Cherrier; Emmanuel Valjent; Denis Hervé; Joanne Darragh; Jean-Christophe C...; Christiane Pages; Arthur J. Simon; Jean-Antoine Girault; Jocelyne Caboche
• Keywords: Conditioned place preference; Immediate early gene

Although the induction of persistent behavioral alterations by drugs abuse requires regulation gene transcription, precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for expression immediate-early genes in striatum response to cocaine and Δ9-tetrahydrocannabinol rewarding properties these drugs. Here we show mice a single injection (10 mg/kg) activates mitogen- stress-activated protein 1 (MSK1) dorsal nucleus accumbens. Cocaine-induced phosphorylation MSK1 threonine 581 cAMP element-binding (CREB) serine 133 (Ser ) were blocked SL327, drug prevents ERK activation. Cocaine increased acetylation histone H4 lysine 5 H3 Ser 10 , demonstrating existence drug-induced chromatin remodeling vivo . In knock-out (KO) CREB blocked, c-Fos dynorphin was prevented, whereas Egr-1 (early growth response-1)/zif268/Krox24 unaltered. MSK1-KO had no obvious neurological defect but displayed contrasted phenotype cocaine. Acute effects dopamine D or 2 agonists Sensitivity low doses, not high conditioned place preference paradigm, locomotor sensitization repeated injections decreased markedly. Our results major striatal kinase, downstream from ERK, responsible required specifically as well sensitization.