Nicotine enhances alcohol intake and dopaminergic responses through \u03b22* and \u03b24* nicotinic acetylcholine receptors

Stefania Tolu,Philippe Faure,Fabio Marti,Nicolas Torquet,Carole Morel,Carole Perrier,Stephanie Pons,Renaud de Beaurepaire

doi:10.1038/srep45116

Abstract

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of β4 * nAChRs, but not β2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (β2−/− and β4−/− mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in β2−/− and β4−/− mice, suggesting that nicotine triggers β2* and β4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.

Highlights

NAChRs are a family of pentameric ligand-gated ion channels made up of different α (α2-α10) and β (β2- β4) subunits which can assemble in multiple combinations[16]
Our interest focused on β2-containing (β2*) and β4 * nAChRs as they show specific DA phenotypes with regards to nicotine reinforcement. β2−/− mice lack the ability to self-administer nicotine and do not display nicotine-induced DA release in the NAcc[17,18,19], while β4−/− mice have been recently implicated in the control of nicotine consumption[20,21]
To what we observed with nicotine[24], a fraction of VTA DA cells were inhibited by alcohol, but the current study focuses on cells that were excited by alcohol

Summary

Introduction

NAChRs are a family of pentameric ligand-gated ion channels made up of different α (α2-α10) and β (β2- β4) subunits which can assemble in multiple combinations[16]. Our interest focused on β2-containing (β2*) and β4 * nAChRs as they show specific DA phenotypes with regards to nicotine reinforcement. Β2−/− mice lack the ability to self-administer nicotine and do not display nicotine-induced DA release in the NAcc[17,18,19], while β4−/− mice have been recently implicated in the control of nicotine consumption[20,21]. The interest for β4*-nAChRs is supported by human genetic studies assessing the implication of this receptor in the vulnerability to nicotine dependence and in the age of initiation for both tobacco and alcohol consumption[6,22,23]. We used transgenic mice to investigate the role of specific nAChRs in alcohol-induced responses and alcohol intake in nicotine-naïve and nicotine-exposed mice

Methods

Results

Conclusion