Venue: Centre Broca
Defense in french
Alice Minard
Team: EMOTIV
INCIA
Thesis supervisor: Stéphanie Caillé Garnier
Title
Neurobiological basis underlying rewarding properties of flavored nicotine in e-cigarettes
Abstract
The electronic cigarette is a device that generates an inhalable aerosol, with or without nicotine, by heating an e-liquid solution Over the past decade, its use has increased considerably among adults. Initially used for smoking cessation purposes, it has also gained popularity among never-smokers. This rise prompts questions about the neurobiological mechanisms underlying the appeal of these products. Given that nicotine itself is mildly reinforcing, olfactory stimuli associated with vaping emerge as prime candidates to explain the appetitive properties of flavored e-liquids. However, while the reward system has been the subject of extensive clinical and preclinical investigations, the olfactory system remains largely understudied in this context. This thesis work aims precisely to fill this gap.
Our hypothesis is that the olfactory tubercle (OT), a brain structure occupying a functional hub position between the olfactory and reward systems and playing a key role in odor-motivated behaviors, constitutes the neurobiological substrate of the appetitive properties of flavored nicotine e-liquids. This thesis thus characterizes the behavioral responses and OT neuronal activity induced by flavored aerosol inhalation in mice.
The first objective consisted of developing an e-liquid vaporization exposure model to identify optimal reward conditions in mice, subsequently enabling exploration of the underlying neural mechanisms. We developed a conditioned place preference behavioral paradigm allowing controlled e-liquid vaporization to reproduce the sensory effects of aerosol inhalation.
The second objective focused on characterizing OT neuronal responses to different e-liquid compositions. c-Fos imaging confirmed the relevance of choosing the OT as a region of interest, as passive exposure to rewarding flavored nicotine e-liquid induced a specific increase in its neuronal activity. Subsequently, examination of dynamic OT neuronal activity by fiber photometry coupled with a cellular activity marker during e-liquid vaporization showed that all aerosols increase OT activity. However, an e-liquid with nicotine alone induces a biphasic response with an initial inhibition followed by increased OT activity. Adding flavor to nicotine completely abolishes the activity decrease. Measurement of OT dopaminergic (DA) neuromodulation under the same conditions showed that nicotine alone drastically increases OT DA activity, whereas flavored nicotine induces a slight increase followed by a strong reduction. The olfactory reward signal produced by flavored nicotine vaporization thus appears to involve an inverse correlation between global activity and OT DA activity.
The third objective consisted of examining dynamic OT activity during free exploration behavior guided by various olfactory stimuli including e-liquids. In the presence of nicotine, flavored or not, voluntary exploration is reduced. While all tested olfactory stimuli increase OT calcium activity without significant differences between conditions, dopaminergic neuromodulation shows reduced amplitude but remains specific for each stimulus.
In conclusion, this thesis work demonstrates the sensory and rewarding properties of flavors in e-liquids by combining the study of behaviors important in vaping initiation with the underlying neurobiological substrate. Flavors are modulators of the olfactory reward neurobiological circuit that can have a non-negligible impact on e-cigarette initiation.
Keywords: Flavored nicotine, e-cigarette, addiction vulnerability, olfactory reward, olfactory tubercle
Jury
- CAILLE-GARNIER Stéphanie, Directrice de recherche, Université de Bordeaux, Directrice de thèse
- MARTI Fabio, Maître de conférences, Sorbonne Université, Paris, Rapporteur
- MANDAIRON Nathalie, Directrice de recherche, Centre de recherche en Neurosciences de Lyon, Rapporteure
- POURCHEZ Jérémie, Directeur de recherche, École nationale supérieure des Mines de St-Etienne, Examinateur
- HARELL Evan, Chargé de recherche, IINS – Université de Bordeaux, Examinateur