TY - JOUR T1 - Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signalling JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.084863 SP - mol.113.084863 AU - Ginetta Collo AU - Federica Bono AU - Laura Cavalleri AU - Laura Plebani AU - Stefania Mitola AU - Emilio Merlo Pich AU - Mark J. Millan AU - Michele Zoli AU - Uwe Maskos AU - PierFranco Spano AU - Cristina Missale Y1 - 2013/03/29 UR - http://molpharm.aspetjournals.org/content/early/2013/03/29/mol.113.084863.abstract N2 - Though long-term exposure to nicotine is highly addictive, one "beneficial" consequence of chronic tobacco use is a reduced risk for Parkinson's disease. Interestingly, these effects both reflect structural and functional plasticity of brain circuits controlling reward and motor behavior, and specifically recruitment of nicotinic acetylcholine receptors (nAChR) in mesencephalic dopaminergic neurons. Since the underlying cellular mechanisms are poorly understood, we addressed this issue employing primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1-10 μM) for 72 hr in vitro increased dendritic arborization and soma size in primary cultures. These effects were blocked by mecamylamine and dihydro-β-erythroidine, but not methyllycaconitine. The involvement of α4β2 nAChR was supported by the lack of nicotine-induced structural remodeling in neurons from α4 null mutant mice (KO). Challenge with nicotine triggered phosphorylation of the extracellular signal-regulated kinase (ERK) and the thymoma viral proto-oncogene (Akt) followed by activation of the mTORC1-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent upon functional DA D3 receptor (D3R) since nicotine was inactive both in cultures from D3R KO mice and following pharmacologic blockade with D3R antagonist SB-277011-A (50 nM). Finally, exposure to nicotine in utero (5 mg/kg/day for 5 days) resulted in increased soma area of DAergic neurons of newborn mice, effects not observed in D3KO mice. These findings indicate that nicotine-induced structural plasticity in mesencephalic dopaminergic neurons involves α4β2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling. ER -