Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine.

Exley R., Maubourguet N., David V., Eddine R., Evrard A., Pons S., Marti F., Threlfell S., Cazala P., McIntosh JM., Changeux J-P., Maskos U., Cragg SJ., Faure P.

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.

DOI

10.1073/pnas.1103000108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

03/05/2011

Volume

108

Pages

7577 - 7582

Keywords

Analysis of Variance, Animals, Autoradiography, Dopamine, Electrophysiology, Genetic Vectors, Lentivirus, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Nicotine, Receptors, Nicotinic, Ventral Tegmental Area

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