β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement
J. Neurosci.. 2020-03-17; 40(17): 3465-3477
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Husson M(1)(2), Harrington L(3)(4), Tochon L(1)(2), Cho Y(1)(2), Ibañez-Tallon I(5), Maskos U(3), David V(6)(2).
(1)Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, 33615 Pessac, France.
(2)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5287, 33615 Pessac, France.
(3)Département de Neuroscience, Institut Pasteur, Unité Neurobiologie Intégrative des Systèmes Cholinergiques, 75724 Paris, France.
(4)Sorbonne Université, Collège Doctoral, 75005 Paris, France.
(5)Laboratory of Molecular Biology, the Rockefeller University, New York, New York 10065.
(6)Université de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, 33615 Pessac, France
Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene 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 STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene 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.
Copyright © 2020 the authors.