Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine

Stefania Fasano, Angela D'Antoni, Paul C. Orban, Emmanuel Valjent, Elena Putignano, Hugo Vara, Tommaso Pizzorusso, Maurizio Giustetto, Bongjune Yoon, Paul Soloway, Rafael Maldonado, Jocelyne Caboche, Riccardo Brambilla

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91 Citations (Scopus)


Background: Ras-extracellular signal-regulated kinase (Ras-ERK) signaling is central to the molecular machinery underlying cognitive functions. In the striatum, ERK1/2 kinases are co-activated by glutamate and dopamine D1/5 receptors, but the mechanisms providing such signaling integration are still unknown. The Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal specific activator of Ras-ERK signaling, is a likely candidate for coupling these neurotransmitter signals to ERK kinases in the striatonigral medium spiny neurons (MSN) and for modulating behavioral responses to drug abuse such as cocaine. Methods: We used genetically modified mouse mutants for Ras-GRF1 as a source of primary MSN cultures and organotypic slices, to perform both immunoblot and immunofluorescence studies in response to glutamate and dopamine receptor agonists. Mice were also subjected to behavioral and immunohistochemical investigations upon treatment with cocaine. Results: Phosphorylation of ERK1/2 in response to glutamate, dopamine D1 agonist, or both stimuli simultaneously is impaired in Ras-GRF1-deficient striatal cells and organotypic slices of the striatonigralMSNcompartment. Consistently, behavioral responses to cocaine are also affected in mice deficient for Ras-GRF1 or overexpressing it. Both locomotor sensitization and conditioned place preference are significantly attenuated in Ras-GRF1-deficient mice, whereas a robust facilitation is observed in overexpressing transgenic animals. Finally, we found corresponding changes in ERK1/2 activation and in accumulation of FosB/ΔFosB, a well-characterized marker for long-term responses to cocaine, in MSN from these animals. Conclusions: These results strongly implicate Ras-GRF1 in the integration of the two main neurotransmitter inputs to the striatum and in the maladaptive modulation of striatal networks in response to cocaine.

Original languageEnglish
Pages (from-to)758-768
Number of pages11
JournalBiological Psychiatry
Issue number8
Publication statusPublished - 2009 Oct 15

Bibliographical note

Funding Information:
This work was supported by the Italian Ministry for the University and Research (MIUR) (RB, TP, and MG) and by the Mariani Foundation for Neurological Research (RB). We would like to thank Steven Clapcote for the GENA53 mice and Marzia Indrigo for excellent technical assistance.


  • Cocaine responses
  • Dopamine
  • ERK1/2 signaling
  • Glutamate
  • Ras-GRF1
  • Striatum

ASJC Scopus subject areas

  • Biological Psychiatry


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