β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement

Autor: Marianne Husson, Léa Tochon, Inés Ibañez-Tallon, Lauriane Harrington, Yoon H. Cho, Uwe Maskos, Vincent David
Přispěvatelé: Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Rockefeller University [New York], This work was supported by FP7 ERANET program (NICO-GENE), the Institut Pasteur, Center National de la Recherche Scientifique CNRS UMR 3571 (U.M.) and CNRS UMR 5287 (V.D.) and the Agence Nationale pour la Recherche (ANR-10-BLAN-1437, project 'NICOSTOP'), the French National Cancer Institute (INCa-CANCEROPOLE-TABAC-01-16022), the EC FP7 Grant agreement 'NeuroCypres' project, Fondation EDF, the Fondation des Treilles, and the Foundation for Medical Research FMR. U.M. is a member of the Laboratory of Excellence, Bio-Psy Labex, as such this work was supported by French state funds managed by the Agence Nationale pour la Recherche (ANR) within the Investissements d'Avenir program under reference ANR-11-IDEX- 0004-02. The team of U.M. is part of the Ecole des Neurosciences de Paris Ile-de-France Network. Work in New York was supported by National Institute on Drug Abuse Grant P30DA035756. We thank Stéphanie Pons for constant support and discussions, and Martine Soudant for technical assistance., ANR-10-BLAN-1437,NICOSTOP(2010), European Project: 202088,EC:FP7:HEALTH,FP7-HEALTH-2007-A,NEUROCYPRES(2008), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
medicine.medical_treatment
Self Administration
Receptors
Nicotinic
Pharmacology
Discrimination Learning
Nicotine
Mice
[SCCO]Cognitive science
0302 clinical medicine
Nicotinic Agonists
ComputingMilieux_MISCELLANEOUS
Research Articles
reward
media_common
Mice
Knockout
[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior
Behavior
Animal
General Neuroscience
[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Ventral tegmental area
Nicotinic acetylcholine receptor
medicine.anatomical_structure
Habenula
Nicotine withdrawal
addiction
reward Significance Statement
medicine.drug
nicotinic receptors
Interpeduncular nucleus
media_common.quotation_subject
Nerve Tissue Proteins
Motor Activity
Self-Control
interpeduncular nucleus
03 medical and health sciences
mental disorders
medicine
Animals
Motivation
habenula
business.industry
[SCCO.NEUR]Cognitive science/Neuroscience
Addiction
Ventral Tegmental Area
medicine.disease
030104 developmental biology
Conditioning
Operant
Smoking cessation
business
030217 neurology & neurosurgery
nicotine
Zdroj: Journal of Neuroscience
Journal of Neuroscience, 2020, 40 (17), pp.3465-3477. ⟨10.1523/JNEUROSCI.0356-19.2020⟩
J Neurosci
Journal of Neuroscience, Society for Neuroscience, 2020, 40 (17), pp.3465-3477. ⟨10.1523/JNEUROSCI.0356-19.2020⟩
ISSN: 1529-2401
0270-6474
DOI: 10.1523/jneurosci.0356-19.2020
Popis: Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in theCHRNA5-CHRNA3-CHRNB4gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.SIGNIFICANCE STATEMENTHuman genetic studies have provided strong evidence for a relationship between variants in theCHRNA5-CHRNA3-CHRNB4gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a “stop” signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.
Databáze: OpenAIRE
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