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Cited by 614Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchParkinson's Disease Mechanisms and Treatments

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

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Valjent, Emmanuel, Pascoli, Vincent, Svenningsson, Per, Paul, Surojit, Enslen, Hervé, Corvol, Jean-Christophe, Stipanovich, Alexandre, Caboche, Jocelyne +5 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0408305102PMC PMC544317
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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 Δ 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.

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Authors
Valjent, E., Pascoli, V., Svenningsson, P., Paul, S., Enslen, H., Corvol, J.-C., Stipanovich, A., Caboche, J., Lombroso, P. J., Nairn, A. C., Greengard, P., Hervé, D., & Girault, J.-A.
Affiliations
Inserm (FR)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-12-17
Volume
102
Issue
2
Pages
491-496
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0408305102
PMC
PMC544317
OpenAlex
W2159891593
Cited by
614
References
40
Citations by year
2026: 1 · 2025: 9 · 2024: 15 · 2023: 15 · 2022: 20 · 2021: 26 · 2020: 25 · 2019: 22 · 2018: 18 · 2017: 26 · 2016: 23 · 2015: 33 · 2014: 38 · 2013: 25 · 2012: 44
FWCI
11.17
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • National Institute of Mental Health (MH40899, R01MH052711, P01MH040899, K02MH001527)
  • National Institute on Drug Abuse (DA10044, P01DA010044)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
ERK activation, DARPP-32, protein phosphatase 1, NMDA receptor, dopamine D1 receptor, nucleus accumbens, dorsal striatum, medium spiny neurons, cocaine, amphetamine, locomotor sensitization, drug addiction, synaptic plasticity, psychostimulants
MeSH terms
Animals, Cocaine, Corpus Striatum, Dextroamphetamine, Dopamine, Enzyme Activation, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Phosphoproteins, Phosphorylation, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Glutamic Acid, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Dopamine and cAMP-Regulated Phosphoprotein 32

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