title: Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.
abstract: 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.
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris Cedex, France.|CNRS, UMR 3571, Paris Cedex, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Harrington
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Viñals
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrera-Solís
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Flores
authors.affiliation: Neuroscience Paris Seine NPS, CNRS UMR8246, INSERM U1130 UPMC UM 119, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Morel
authors.affiliation: Neuroscience Paris Seine NPS, CNRS UMR8246, INSERM U1130 UPMC UM 119, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tolu
authors.affiliation: Neuroscience Paris Seine NPS, CNRS UMR8246, INSERM U1130 UPMC UM 119, Equipe Neurophysiologie et comportement (NPC), Université P. et M. Curie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Faure
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris Cedex, France.|CNRS, UMR 3571, Paris Cedex, France.
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.affiliation: Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.|Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019262:Habenula / Q000187:drug effects / Q000378:metabolism*; D066268:Interpeduncular Nucleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012054:Reinforcement, Psychology; D014161:Transduction, Genetic
chemical_list: C486720:Chrnb4 protein, mouse; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D009538:Nicotine; D010735:Phosphoglycerate Kinase; D004298:Dopamine