Selective re-expression of β2 nicotinic acetylcholine receptor subunits in the ventral tegmental area of the mouse restores intravenous nicotine self-administration

Beta-2 (β2) nicotinic acetylcholine receptor subunits have been particularly related with nicotine reinforcement. However, the importance of these subunits in the chronic aspects of nicotine addiction has not been established. In this study we evaluated the role of ventral tegmental area (VTA) β2 receptor subunits in the acquisition and maintenance of nicotine self-administration. We used an operant mouse model of intravenous self-administration of different doses of nicotine (15, 30, and 60 μg/kg/infusion) during 10 days in constitutive knockout mice lacking β2 receptor subunits (β2KO), wild-type (WT) controls, mice with β2 receptor subunits re-expressed in the VTA using a lentiviral vector (β2-VEC), and control knockout mice with a sham injection (KO-GFP). The results showed that β2KO mice did not reliably acquire nicotine self-administration at any of the doses tested, while WT controls showed dose-dependent acquisition of this behaviour. β2-VEC mice readily acquired and maintained nicotine self-administration at the effective dose of 15 μg/kg/infusion, while sham KO-GFP mice did not. The recovery of the WT phenotype by the re-expression of β2 receptor subunits within the VTA supports the role of this specific population in nicotine reinforcement, and reveals that they are sufficient for the acquisition and maintenance of systemic nicotine self-administration.This work was supported by the Spanish “Instituto de Salud Carlos III” (RD06/001/001 and PI10/01708), FEDER funds, and Ministerio de Ciencia e Innovación (SAF2007-64062), the Catalan Government (SGR2009-00131), an FP7 ERANET programme (NICO-GENE), the ICREA Foundation (ICREA Academia-2008), and a post-doctoral fellowship from CONACyT to AH