Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration

Abstract

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different α subunit partners of β2 (i.e., α4 and α6), the homo-pentameric α7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 μg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the β2, α4, α6 and α7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, β2-VEC mice with the β2 subunit re-expressed exclusively in the VTA, α4-VEC mice with selective α4 re-expression in the VTA, α6-VEC mice with selective α6 re-expression in the VTA, and α7-KO mice promptly self-administer nicotine intravenously, whereas β2-KO, β2-VEC in the substantia nigra, α4-KO and α6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of α4β2- and α6β2-subunit containing nicotinic receptors (α4β2*- and α6β2*-nAChRs), but not α7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice. Copyright © 2008 Society for Neuroscience.