title: Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling.
abstract: Although long-term exposure to nicotine is highly addictive, one beneficial consequence of chronic tobacco use is a reduced risk for Parkinson's disease. Of interest, 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. Because the underlying cellular mechanisms are poorly understood, we addressed this issue with use of primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1-10 μM) for 72 hours 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 mammalian target of rapamycin complex 1 (mTORC1)-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride] resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent on functional DA D3 receptor (D3R), because nicotine was inactive both in cultures from D3R KO mice and after pharmacologic blockade with D3R antagonist trans-N-4-2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethylcyclohexyl-4-quinolinecarboxamide (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 D3 receptor null mutant mice mice. These findings indicate that nicotine-induced structural plasticity at mesencephalic dopaminergic neurons involves α4β2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling.
authors.affiliation: Department of Molecular and Translational Medicine, 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: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pich
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Spano
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D020935:MAP Kinase Signaling System; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D000076222:Mechanistic Target of Rapamycin Complex 1; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D050637:Receptors, Dopamine D3; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases