Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA

This work was supported by the Spanish Instituto de Salud Carlos III (RD06/001/001 and PI10/01708; PI14/00210), FEDER funds, Ministerio de Ciencia e Innovación (#SAF2014-59648-P), the Catalan Government AGAUR (#2014-SGR-1547), Plan Nacional Sobre Drogas, Ministerio de Sanidad, Asuntos Sociales e Igualdad-MSASI (#PNSD- 2013-0068), FP7 ERANET program (NICO-GENE), the ICREA Foundation (ICREA Academia-2008), and a postdoctoral fellowship from CONACyT to AHS. The work in Paris was supported by the Institut Pasteur, Centre National de la Recherche Scientifique CNRS UMR 3571 (UM) and CNRS UMR 8246 (PF), the INSERM U1130 (PF), the Pierre et Marie Curie University (UM119), the Agence Nationale pour la Recherche (ANR Neuroscience), and FP7 ERANET program (NICO-GENE), Grant agreement n009 BLANC 20092009BLANC 20 NeuroCypres" project), Fondation EDF, the Fondation des Treilles, and the Foundation for Medical Research FMR (Equipe FRMDEQ20130326488 to PF). The groups of UM and PF are members of the Bio-Psy Labex. As such this work was supported by French state funds managed by the ANR within the Investissements d'Avenir programme under reference ANR-11-IDEX-0004-02. The teams of UM and PF are part of the École des Neurosciences de Paris Ile-de-France Network. We would like to thank Martine Soudant, Stephanie Pons, and Dulce Real for technical support, and Inés Ibañes-Tallon and Jessica/nAbles for providing the Tg(Chrnb4-cre)OL57Gsat/+ transgenic mice