Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction¹, but nicotine is also known to enhance cognitive performance². Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the 2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying 2-subunit deletions^{3, 4}. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that 2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

1. Unité Récepteurs et Cognition, CNRS URA 2182, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
2. Laboratoire de Neuropharmacologie EA3544, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry Cedex, France
3. Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de Bordeaux-I, Avenue des Facultés, 33405 Talence Cedex, France
4. Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégéneratifs (LGN), CNRS-UMR 7091, Hôpital de la Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75013 Paris, France
5. †Present addresses: Isotopic Imaging, Biochemical and Pharmacological Unit, and Imagene Program, Service Hospitalier Frédéric Joliot, 91401 Orsay, France (N.D.); Laboratoire d'oculogénétique, Hôpital Ophtalmique Jules Gonin, 1004 Lausanne, Switzerland (A.-P.B.)

Correspondence to: J.-P. Changeux¹ Correspondence and requests for materials should be addressed to J.-P.C. (Email: changeux@pasteur.fr).

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