title: Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum.
abstract: Many drugs of abuse exert their addictive effects by increasing extracellular dopamine in the nucleus accumbens, where they likely alter the plasticity of corticostriatal glutamatergic transmission. This mechanism implies key molecular alterations in neurons in which both dopamine and glutamate inputs are activated. Extracellular signal-regulated kinase (ERK), an enzyme important for long-term synaptic plasticity, is a good candidate for playing such a role. Here, we show in mouse that d-amphetamine activates ERK in a subset of medium-size spiny neurons of the dorsal striatum and nucleus accumbens, through the combined action of glutamate NMDA and D1-dopamine receptors. Activation of ERK by d-amphetamine or by widely abused drugs, including cocaine, nicotine, morphine, and Delta(9)-tetrahydrocannabinol was absent in mice lacking dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32). The effects of d-amphetamine or cocaine on ERK activation in the striatum, but not in the prefrontal cortex, were prevented by point mutation of Thr-34, a DARPP-32 residue specifically involved in protein phosphatase-1 inhibition. Regulation by DARPP-32 occurred both upstream of ERK and at the level of striatal-enriched tyrosine phosphatase (STEP). Blockade of the ERK pathway or mutation of DARPP-32 altered locomotor sensitization induced by a single injection of psychostimulants, demonstrating the functional relevance of this regulation. Thus, activation of ERK, by a multilevel protein phosphatase-controlled mechanism, functions as a detector of coincidence of dopamine and glutamate signals converging on medium-size striatal neurons and is critical for long-lasting effects of drugs of abuse.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale and Université Pierre et Marie Curie U536, "Signal Transduction and Plasticity in the Nervous System," Institut du Fer à Moulin, 17 Rue du Fer à Moulin, 75005 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.forename: Vincent
authors.initials: V
authors.lastname: Pascoli
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Surojit
authors.initials: S
authors.lastname: Paul
authors.forename: Hervé
authors.initials: H
authors.lastname: Enslen
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Alexandre
authors.initials: A
authors.lastname: Stipanovich
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Caboche
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Girault
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000201:enzymology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004789:Enzyme Activation; D018698:Glutamic Acid / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D003042:Cocaine; D003913:Dextroamphetamine; D004298:Dopamine