Distinct contributions of nicotinic acetylcholine receptor subunit α4 and subunit α6 to the reinforcing effects of nicotine

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 alpha 4- and subunit alpha 6-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 alpha 4 subunit, but not the alpha 6 subunit, is necessary for ICSA and nicotine-induced bursting of VTA DAergic neurons, whereas subunits alpha 4 and alpha 6 together regulate the activity dependence of DA transmission in the NAc. These data suggest that alpha 4-dominated enhancement of burst firing in DA neurons, relayed by DA transmission in NAc that is gated by nAChRs containing alpha 4 and alpha 6 subunits, underlies nicotine self-administration and its long-term maintenance.