Pre-synaptic dopamine D3 receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways

Authors

  • Ginetta Collo,

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
    2. Woman Health Center-Camillo Golgi Foundation, University of Brescia, Brescia, Italy
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  • Federica Bono,

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
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  • Laura Cavalleri,

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
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  • Laura Plebani,

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
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  • Emilio Merlo Pich,

    1. Neuronal Targets DPU, Respiratory TAU, GlaxoSmithKline, King of Prussia, Pennsylvania, USA
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  • Mark J. Millan,

    1. Division of Psychopharmacology, Institut de Recherches Servier, Croissy-Sur-Seine (Paris), France
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  • Pier Franco Spano,

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
    2. Woman Health Center-Camillo Golgi Foundation, University of Brescia, Brescia, Italy
    3. IRCCS San Camillo Hospital, Venice, Italy
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  • Cristina Missale

    1. Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy
    2. Woman Health Center-Camillo Golgi Foundation, University of Brescia, Brescia, Italy
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Address correspondence and reprint requests to Ginetta Collo, Department of Biomedical Sciences and Biotechnologies, National Institute of Neuroscience-Italy, and Woman Health Center-Camillo Golgi Foundation, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. E-mail: collo@med.unibs.it

Abstract

J. Neurochem. (2012) 120, 765–778.

Abstract

Exposure to psychostimulants results in neuroadaptive changes of the mesencephalic dopaminergic system including morphological reorganization of dopaminergic neurons. Increased dendrite arborization and soma area were previously observed in primary cultures of mesencephalic dopaminergic neurons after 3-day exposure to dopamine agonists via activation of D3 autoreceptors (D3R). In this work, we showed that cocaine significantly increased dendritic arborization and soma area of dopaminergic neurons from E12.5 mouse embryos by activating phosphorylation of extracellular signal-regulated kinase (ERK) and thymoma viral proto-oncogene (Akt). These effects were dependent on functional D3R expression because cocaine did not produce morphological changes or ERK/Akt phosphorylation neither in primary cultures of D3R mutant mice nor following pharmacologic blockade with D3R antagonists SB-277011-A and S-33084. Cocaine effects on morphology and ERK/Akt phosphorylation were inhibited by pre-incubation with the phosphatidylinositol 3-kinase inhibitor LY294002. These observations were corroborated in vivo by morphometrical assessment of mesencephalic dopaminergic neurons of P1 newborns exposed to cocaine from E12.5 to E16.5. Cocaine increased the soma area of wild-type but not of D3R mutant mice, supporting the translational value of primary culture. These findings indicate a direct involvement of D3R and ERK/Akt pathways as critical mediators of cocaine-induced structural plasticity, suggesting their involvement in psychostimulant addiction.

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