Impact of chemical flavorants on reinforcement-related behavior in an adolescent mouse model of vaping self-administration.

Electronic nicotine delivery systems (ENDSs) are a unique from combustible cigarettes due to the availability of flavor options which make these devices more attractive. Prior preclinical investigations have determined that menthol and green apple flavorants can enhance nicotine reward and reinforcement by altering dopamine transmission via nicotinic acetylcholine receptor modulation in reward-mediating brain areas. In this study, we investigated the impact of vanilla (vanillin and ethyl vanillin) and cherry (ethyl vanillin, vanillin, ethyl acetate, ethyl maltol, and maltol) flavors on reinforcement-related behavior with and without nicotine. Male and female adolescent C57BL/6J mice were used in an e-Vape self-administration assay. Four combinations were shown to increase reinforcement-related behavior: nicotine plus menthol, nicotine plus cherry, nicotine plus vanilla, and vanilla alone. We observed that zero-nicotine cherry-flavored ENDSs did not produce robust reinforcement-related behavior when compared with control vapor. We observed that zero-nicotine vanilla-flavored ENDSs did produce reinforcement-related behavior in adolescent male and female mice; the addition of nicotine did not produce a significant difference in active nose pokes or deliveries but did have increased active-to-inactive ratio. Additionally, we found that vanilla alone was able to modulate tonic and phasic release of dopamine in the nucleus accumbens core. We also looked at the physical interactions of green apple and vanilla flavors on nicotinic subunits. These data provide additional evidence that some chemical flavors promote vaping-related behaviors without the inclusion of nicotine. SIGNIFICANCE STATEMENT: The e-Vape self-administration paradigm is a translationally relevant method of investigating the impact of different flavorants on nicotine use. Because most electronic nicotine delivery system users vape flavored nicotine products, it raises questions about how chemical flavorants alter nicotine addiction and if they increase abuse liability themselves. In accordance with our prior findings on green apple, vanilla flavorants are able to cause changes in reward-related behaviors in the absence of nicotine potentially through altering dopamine release in the nucleus accumbens.