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PNAS 102 (2): 491-496

Copyright © 2005 by the National Academy of Sciences.

From The Cover

NEUROSCIENCE

Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum

Emmanuel Valjent *, Vincent Pascoli *, Per Svenningsson {dagger}, Surojit Paul {ddagger}, Hervé Enslen *, Jean-Christophe Corvol *, Alexandre Stipanovich *, Jocelyne Caboche §, Paul J. Lombroso {ddagger}, Angus C. Nairn {dagger}, ¶, Paul Greengard {dagger}, ||, Denis Hervé *, and Jean-Antoine Girault *, ||

*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; {dagger}Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021; {ddagger}Child Study Center, Yale University School of Medicine, New Haven, CT 06510; §Laboratoire Signalisation Neuronale et Régulations Géniques, Centre National de la Recherche Scientifique/Université Pierre et Marie Curie, Unité Mixte de Recherche 7102, 9 Quai Saint Bernard, 75005 Paris, France; and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508

Contributed by Paul Greengard, November 8, 2004

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 Mr 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.

Key Words: dopamine D1 receptor • drug addiction • NMDA receptor • nucleus accumbens • protein kinase

Author contributions: E.V., V.P., A.C.N., D.H., and J.-A.G. designed research; E.V., V.P., H.E., J.-C.C., A.C.N., and A.S. performed research; P.S., S.P., J.C., P.J.L., A.C.N., and P.G. contributed new reagents/analytic tools; E.V., D.H., and J.-A.G. analyzed data; and E.V., A.C.N., P.G., D.H., and J.-A.G. wrote the paper.

Abbreviations: d-amph, d-amphetamine; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of Mr 32,000; D1R, dopamine D1 receptor; ERK, extracellular signal-regulated kinase; GluR1, glutamate receptor 1; MEK, mitogen-activated protein kinase/ERK kinase; MSN, medium-size spiny neuron; NMDAR, NMDA receptor; P-ERK, phospho-ERK; PKA, cAMP-dependent protein kinase; PP-1, protein phosphatase-1; STEP, striatal-enriched tyrosine phosphatase; THC, {Delta}9-tetrahydrocannabinol.

See Commentary on page 253.

|| To whom correspondence may be addressed. E-mail: greengd{at}rockefeller.edu or girault{at}fer-a-moulin.inserm.fr.

© 2005 by The National Academy of Sciences of the USA

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