Summary: A new preclinical study from Marshall University shows that certain e-cigarette flavorings — notably vanilla and cherry compounds — can provoke reward-seeking behaviors in adolescent mice even when no nicotine is present. The research indicates that some flavor chemicals activate the brain’s dopamine system and interact with nicotinic acetylcholine receptors, raising concerns that nicotine-free flavored vapes could still encourage addiction-like patterns in teens.
Vanilla-flavored vapor stood out in the study: it significantly reinforced vaping-like behaviors on its own, independent of nicotine. These results underscore potential risks associated with flavored vaping products marketed as nicotine-free and highlight the need for careful scrutiny of flavor additives.
Key Facts:
- Flavor effects without nicotine: Vanilla and certain cherry-related chemicals increased reinforcement-related behaviors in adolescent mice even in the absence of nicotine.
- Brain mechanisms: Flavorants influenced dopamine release in the nucleus accumbens and altered nicotinic acetylcholine receptor (nAChR) function, both of which are implicated in reward and addiction.
- Youth vulnerability: Flavored, nicotine-free e-cigarette aerosols may still promote addiction-like responses in adolescents, based on this animal model.
Source: Marshall University
Study overview: Researchers at the Marshall University Joan C. Edwards School of Medicine conducted a controlled preclinical investigation, recently published in the Journal of Pharmacology and Experimental Therapeutics, to determine whether common e-cigarette flavor chemicals alter reinforcement-related behavior in adolescent mice. Using a voluntary inhalation model designed to mimic human vaping behavior, the team tested flavored aerosols both with and without nicotine.
The study used adolescent male and female C57BL/6J mice in an e-Vape® self-administration (EVSA) assay, a behavioral model that permits voluntary inhalation of flavored aerosols. The investigators measured active responses (nose pokes) and delivery events to assess reinforcement-related behavior. Mice exposed to vanillin or benzaldehyde exhibited significantly higher active responses than control animals, even when the aerosol contained no nicotine.
Four flavor-nicotine conditions produced clear increases in reinforcement-related behavior: nicotine combined with menthol, nicotine with cherry, nicotine with vanilla, and vanilla flavor alone without nicotine. Notably, nicotine-free cherry flavor did not produce robust reinforcement compared with control vapor, while nicotine-free vanilla did. When vanilla was paired with nicotine, the presence of nicotine did not significantly increase the number of active responses or deliveries versus vanilla alone, although nicotine did alter the ratio of active to inactive responses.
At the neurochemical level, the team found that vanilla compounds modulated both tonic and phasic dopamine release in the nucleus accumbens core, a central reward region. Separate molecular assays also showed that green apple and vanilla flavor chemicals can physically interact with nicotinic receptor subunits, providing a potential mechanistic explanation for how flavorants alter reward circuitry.
“These findings are significant because they demonstrate that some electronic nicotine delivery system (ENDS) flavors can modulate the brain’s dopamine system — specifically in the nucleus accumbens, a key reward center — even without nicotine present,” said lead investigator Brandon J. Henderson, Ph.D., associate professor of biomedical sciences at the Joan C. Edwards School of Medicine. “This raises important questions about the potential for addiction-like behaviors in adolescents who use flavored vape products marketed as nicotine-free.”
The authors emphasize that these preclinical data add to a growing body of evidence suggesting that flavor additives do more than provide scent and taste: some actively change brain responses linked to reward and dependence, particularly during adolescence when the brain is more sensitive to reinforcing stimuli.
In addition to Dr. Henderson, co-authors include Marshall University medical students Dami Adeshina, Gabrielle Hammers, Sean Hill, Sydney McSweeney, Sabrina Swenson, and Sarah Maddox, along with Ph.D. students Nathan Olszewski and Samuel Tetteh-Quarshie. Funding for the study was provided by the National Institute on Drug Abuse (grant DA050717).
About this neuroscience research news
Author: Sheanna Spence
Source: Marshall University
Contact: Sheanna Spence, Marshall University
Image credit: Neuroscience News
Original research (open access): Impact of chemical flavorants on reinforcement-related behavior in an adolescent mouse model of vaping self-administration — Brandon J. Henderson et al. Journal of Pharmacology and Experimental Therapeutics. DOI: 10.1016/j.jpet.2025.103651
Abstract
Impact of chemical flavorants on reinforcement-related behavior in an adolescent mouse model of vaping self-administration
Electronic nicotine delivery systems (ENDS) differ from combustible tobacco primarily because of the wide variety of flavor options that can increase product appeal. Previous preclinical work has shown that menthol and green apple flavorants can enhance nicotine reward and reinforcement by modifying dopamine transmission through nicotinic receptor modulation in brain reward regions.
This study examined vanilla-related compounds (vanillin and ethyl vanillin) and cherry-related mixtures (including ethyl vanillin, vanillin, ethyl acetate, ethyl maltol, and maltol) to determine their effects on reinforcement-related behavior with and without nicotine. Using an EVSA assay in adolescent male and female C57BL/6J mice, researchers observed that four conditions increased reinforcement-related responding: nicotine plus menthol, nicotine plus cherry, nicotine plus vanilla, and vanilla alone. Zero-nicotine cherry flavor did not produce robust reinforcement compared with control vapor, while zero-nicotine vanilla did produce reinforcement-related behavior in both sexes.
Vanilla alone altered both tonic and phasic dopamine release in the nucleus accumbens core. Additional assays revealed physical interactions between green apple and vanilla flavorants and nicotinic receptor subunits. Together, these data provide further evidence that some flavor chemicals can promote vaping-related behaviors in adolescent animals even in the absence of nicotine.