title: Pre-synaptic dopamine D(3)  receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways.
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.
authors.affiliation: Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, University of Brescia, Brescia, Italy. collo@med.unibs.it
authors.forename: Ginetta
authors.initials: G
authors.lastname: Collo
authors.forename: Federica
authors.initials: F
authors.lastname: Bono
authors.forename: Laura
authors.initials: L
authors.lastname: Cavalleri
authors.forename: Laura
authors.initials: L
authors.lastname: Plebani
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pich
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Spano
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine; D015259:Dopamine Agents / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014316:Tritium / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D050637:Receptors, Dopamine D3; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine; D004298:Dopamine