Husson M, Harrington L, Tochon L, Cho Y, Ibañez-Tallon I, Maskos U, David V.β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement. J Neurosci. 2020 Apr 22;40(17):3465-3477. doi: 10.1523/JNEUROSCI.0356-19.2020.
This article was recently awarded with a F1000 recommendation for exceptional importance:
https://facultyopinions.com/prime/737584784
Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNΒ4 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. 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 Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by injecting nicotine directly 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. Normal, WT levels of nicotine ICSA are restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that the β4 subunit is a critical modulator of reward-related behaviors, and that β4*nAChRs may provide a promising novel drug target for smoking cessation.
