Crucial Role of α4 and α6 Nicotinic Acetylcholine Receptor Subunits from Ventral Tegmental Area in Systemic Nicotine Self-Administration

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novelin vivoparadigms 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 (VECmice). We show that WT mice, β2-VECmice with the β2 subunit re-expressed exclusively in the VTA, α4-VECmice with selective α4 re-expression in the VTA, α6-VECmice with selective α6 re-expression in the VTA, and α7-KO mice promptly self-administer nicotine intravenously, whereas β2-KO, β2-VECin 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.