Transient and rapid activation of Akt/GSK-3β and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens

Authors

  • Marie-Josèphe Salles,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France
    2. Université Pierre et Marie Curie-Paris 6, Paris, France
    3. Institut du Fer à Moulin, Paris, France
    4. Psychopharmacology Department, Institut de Recherches Servier, Croissy sur Seine, France
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  • Denis Hervé,

    Corresponding author
    1. Université Pierre et Marie Curie-Paris 6, Paris, France
    2. Institut du Fer à Moulin, Paris, France
    • Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France
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  • Jean-Michel Rivet,

    1. Psychopharmacology Department, Institut de Recherches Servier, Croissy sur Seine, France
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  • Sophie Longueville,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France
    2. Université Pierre et Marie Curie-Paris 6, Paris, France
    3. Institut du Fer à Moulin, Paris, France
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  • Mark J. Millan,

    1. Psychopharmacology Department, Institut de Recherches Servier, Croissy sur Seine, France
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  • Jean–Antoine Girault,

    1. Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France
    2. Université Pierre et Marie Curie-Paris 6, Paris, France
    3. Institut du Fer à Moulin, Paris, France
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  • Clotilde Mannoury la Cour

    1. Psychopharmacology Department, Institut de Recherches Servier, Croissy sur Seine, France
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Address correspondence and reprint requests to Denis Hervé, Institut du Fer à Moulin Inserm UMR-S 839, 17 rue du Fer a Moulin, 75005 Paris, France. E-mail: denis.herve@inserm.fr

Abstract

D2/D3 dopamine receptors (D2R/D3R) agonists regulate Akt, but their effects display a complex time-course. In addition, the respective roles of D2R and D3R are not defined and downstream targets remain poorly characterized, especially in vivo. These issues were addressed here for D3R. Systemic administration of quinelorane, a D2R/D3R agonist, transiently increased phosphorylation of Akt and GSK-3β in rat nucleus accumbens and dorsal striatum with maximal effects 10 min after injection. Akt activation was associated with phosphorylation of several effectors of the mammalian target of rapamycin complex 1 (mTORC1): p70S6 kinase, ribosomal protein-S6 (Ser240/244), and eukaryotic initiation factor-4E binding protein-1. The action of quinelorane was antagonized by a D2/D3R antagonist, raclopride, and the selective D3R antagonist S33084, inactive by themselves. Furthermore, no effect of quinerolane was seen in knock-out mice lacking D3R. In drd1a-EGFP transgenic mice, quinelorane activated Akt/GSK-3β in both neurons expressing and lacking D1 receptor. Thus, the stimulation of D3R transiently activates the Akt/GSK-3β pathway in the two populations of medium-size spiny neurons of the nucleus accumbens and dorsal striatum. This effect may contribute to the influence of D3R ligands on reward, cognition, and processes disrupted in schizophrenia, drug abuse, and Parkinson's disease.

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