title: Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine.
abstract: Nicotine is the primary psychoactive component of tobacco. Its reinforcing and addictive properties depend on nicotinic acetylcholine receptors (nAChRs) located within the mesolimbic axis originating in the ventral tegmental area (VTA). The roles and oligomeric assembly of subunit α4- and subunit α6-containing nAChRs in dopaminergic (DAergic) neurons are much debated. Using subunit-specific knockout mice and targeted lentiviral re-expression, we have determined the subunit dependence of intracranial nicotine self-administration (ICSA) into the VTA and the effects of nicotine on dopamine (DA) neuron excitability in the VTA and on DA transmission in the nucleus accumbens (NAc). We show that the α4 subunit, but not the α6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits α4 and α6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that α4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing α4 and α6 subunits, underlies nicotine self-administration and its long-term maintenance.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Exley
authors.forename: Nicolas
authors.initials: N
authors.lastname: Maubourguet
authors.forename: Vincent
authors.initials: V
authors.lastname: David
authors.forename: Raphaël
authors.initials: R
authors.lastname: Eddine
authors.forename: Alexis
authors.initials: A
authors.lastname: Evrard
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pons
authors.forename: Fabio
authors.initials: F
authors.lastname: Marti
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.forename: Pierre
authors.initials: P
authors.lastname: Cazala
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
authors.forename: Philippe
authors.initials: P
authors.lastname: Faure
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D004298:Dopamine / Q000378:metabolism; D004594:Electrophysiology; D005822:Genetic Vectors / Q000235:genetics; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D004298:Dopamine; D009538:Nicotine; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6