Chemical Flavorants in Vaping Products Alter Neurobiology in a Sex-Dependent Manner to Promote Vaping-Related Behaviors.

Electronic nicotine delivery systems (ENDS) are distinctly different from combustible cigarettes because of the availability of flavor options. Subjective measures have been used to demonstrate that adults and adolescents prefer flavors for various reasons; (1) they are pleasing and (2) they mask the harshness of nicotine. Despite this, there have been few investigations into the molecular interactions that connect chemical flavorants to smoking or vaping-related behaviors. Here, we investigated the effects of three chemical flavorants (hexyl acetate, ethyl acetate, and methylbutyl acetate) that are found in green apple (GA) ENDS e-liquids but are also found in other flavor categories. We used a translationally relevant vapor self-administration mouse model and observed that adult male and female mice self-administered GA flavorants in the absence of nicotine. Using α4-mCherryα6-GFP nicotinic acetylcholine receptor (nAChR) mice, we observed that mice exposed to GA flavorants exhibited a sex-specific increase (upregulation) of nAChRs that was also brain-region specific. Electrophysiology revealed that mice exposed to GA flavorants exhibited enhanced firing of ventral tegmental area dopamine neurons. Fast-scan cyclic voltammetry revealed that electrically stimulated dopamine release in the nucleus accumbens core is increased in mice that are exposed to GA flavorants. These effects were similarly observed in the medial habenula. Overall, these findings demonstrate that ENDS flavors alone change neurobiology and may promote vaping-dependent behaviors in the absence of nicotine. Furthermore, the flavorant-induced changes in neurobiology parallel those caused by nicotine, which highlights the fact that nonmenthol flavorants may contribute to or enhance nicotine reward and reinforcement.