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The Journal of Neuroscience, December 7, 2005, 25(49):11444-11454; doi:10.1523/JNEUROSCI.1711-05.2005

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

Karen Brami-Cherrier,^1 * Emmanuel Valjent,^2 * Denis Hervé,² Joanne Darragh,³ Jean-Christophe Corvol,² Christiane Pages,¹ Arthur J. Simon,³ Jean-Antoine Girault,² and Jocelyne Caboche¹

¹Centre National de la Recherche Scientifique and Université Pierre et Marie Curie, Unité Mixte de Recherche 7102, 75005 Paris, France, ²Institut National de la Santé et de la Recherche Médicale and Université Pierre et Marie Curie, Unité 536, Institut du Fer à Moulin, 75005 Paris, France, and ³Medical Research Council Protein Phosphorylation Unit, University of Dundee, Nethergate, Dundee DD1 SEH, United Kingdom

Although the induction of persistent behavioral alterations by drugs of abuse requires the regulation of gene transcription, the precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for the expression of immediate-early genes in the striatum in response to cocaine and 9-tetrahydrocannabinol and for the rewarding properties of these drugs. Here we show that in mice a single injection of cocaine (10 mg/kg) activates mitogen- and stress-activated protein kinase 1 (MSK1) in dorsal striatum and nucleus accumbens. Cocaine-induced phosphorylation of MSK1 threonine 581 and cAMP response element-binding protein (CREB) serine 133 (Ser¹³³) were blocked by SL327, a drug that prevents ERK activation. Cocaine increased the acetylation of histone H4 lysine 5 and phosphorylation of histone H3 Ser¹⁰, demonstrating the existence of drug-induced chromatin remodeling in vivo. In MSK1 knock-out (KO) mice CREB and H3 phosphorylation in response to cocaine (10 mg/kg) were blocked, and induction of c-Fos and dynorphin was prevented, whereas the induction of Egr-1 (early growth response-1)/zif268/Krox24 was unaltered. MSK1-KO mice had no obvious neurological defect but displayed a contrasted behavioral phenotype in response to cocaine. Acute effects of cocaine and dopamine D₁ or D₂ agonists were unaltered. Sensitivity to low doses, but not high doses, of cocaine was increased in the conditioned place preference paradigm, whereas locomotor sensitization to repeated injections of cocaine was decreased markedly. Our results show that MSK1 is a major striatal kinase, downstream from ERK, responsible for the phosphorylation of CREB and H3 and is required specifically for the induction of c-Fos and dynorphin as well as for locomotor sensitization.

Key words: drug addiction; extracellular signal-regulated kinase; CREB phosphorylation; histone modification; immediate-early genes; long-term behavioral responses

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Received April 29, 2005; revised October 17, 2005; accepted October 18, 2005.

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