Exley_2011_Proc.Natl.Acad.Sci.U.S.A_108_7577

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 alpha4- and subunit alpha6-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 alpha4 subunit, but not the alpha6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits alpha4 and alpha6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that alpha4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing alpha4 and alpha6 subunits, underlies nicotine self-administration and its long-term maintenance.