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

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 beta 2 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 alpha subunit partners of beta 2 (i.e., alpha 4 and alpha 6), the homo-pentameric alpha 7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 mu g free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta 2, alpha 4, alpha 6 and alpha 7 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, beta 2-VEC mice with the beta 2 subunit re-expressed exclusively in the VTA, alpha 4-VEC mice with selective alpha 4 re-expression in the VTA, alpha 6-VEC mice with selective alpha 6 re-expression in the VTA, and alpha 7-KO mice promptly self-administer nicotine intravenously, whereas beta 2-KO, beta 2-VEC in the substantia nigra, alpha 4-KO and alpha 6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha 4 beta 2- and alpha 6 beta 2-subunit containing nicotinic receptors (alpha 4 beta 2*- and alpha 6 beta 2*-nAChRs), but not alpha 7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.