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Pre‐synaptic dopamine D 3 receptor mediates cocaine‐induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways
Author(s) -
Collo Ginetta,
Bono Federica,
Cavalleri Laura,
Plebani Laura,
Merlo Pich Emilio,
Millan Mark J.,
Spano Pier Franco,
Missale Cristina
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07618.x
Subject(s) - dopaminergic , dopamine , mapk/erk pathway , protein kinase b , biology , phosphorylation , microbiology and biotechnology , neuroscience , endocrinology , medicine , chemistry
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 D 3 autoreceptors (D 3 R). 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 D 3 R expression because cocaine did not produce morphological changes or ERK/Akt phosphorylation neither in primary cultures of D 3 R mutant mice nor following pharmacologic blockade with D 3 R 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 D 3 R 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.