| First Author | Husson M | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 17 | Pages | 3465-3477 |
| PubMed ID | 32184221 | Mgi Jnum | J:292861 |
| Mgi Id | MGI:6407223 | Doi | 10.1523/JNEUROSCI.0356-19.2020 |
| Citation | Husson M, et al. (2020) beta4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement. J Neurosci 40(17):3465-3477 |
| abstractText | 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 alpha5, alpha3, and beta4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. beta4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that beta4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. beta4 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, beta4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and beta4KO self-administered more than WT mice, whereas beta4-overexpressing mice avoided nicotine injections. Viral expression of beta4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of beta4KO mice revealed dose- and region-dependent differences: beta4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas beta4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional beta4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of beta4*nAChRs in the MHb-IPN. These data indicate that beta4 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 beta4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of beta4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the beta4 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 beta4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that beta4*nAChRs provide a promising novel drug target for smoking cessation. |
