Abstract
While combustible cigarette smoking has declined, the use of electronic nicotine delivery systems (ENDS) has increased. ENDS are popular among adolescents, and chemical flavorants are an increasing concern due to the growing use of zero-nicotine flavored e-liquids. Despite this, little is known regarding the effects of ENDS flavorants on vaping-related behavior. Following previous studies demonstrating the green apple flavorant, farnesol, enhances nicotine reward and exhibits rewarding properties without nicotine, this work focuses on the green apple flavorant, farnesene, for its impact on vaping-related behaviors. Using adult C57BL/6J mice, genetically modified to contain fluorescent nicotine acetylcholine receptors (nAChRs), and farnesene doses of 0.1, 1.0, and 10 mg/kg, we observed farnesene-alone produces reward-related behavior in both male and female mice. We then performed whole-cell patch-clamp electrophysiology and observed farnesene-induced inward currents in ventral tegmental area (VTA) putative dopamine neurons that were blocked by the nAChR antagonist, DhβE. While the amplitudes of farnesene-induced currents are ∼30% of nicotine’s efficacy, this indicates the potential for some ENDS flavorants to stimulate nAChR function. Additionally, farnesene enhances nicotine’s potency for activating nAChRs on VTA dopamine neurons. This may be due to changes in nAChR stoichiometry as our data suggests a shift toward high-sensitivity α4β2 nAChRs. Consequently, these data show that the green apple flavorant, farnesene, causes reward-related behavior without nicotine through changes in nAChR stoichiometry that results in an enhanced effect of nicotine on VTA dopamine neurons. These results demonstrate the importance of future investigations into ENDS flavorants and their effects on vaping-related behaviors.
SIGNIFICANCE STATEMENT Although combustible cigarette use has decreased by ∼11% in America over the past two decades, the use of electronic nicotine delivery systems (ENDS) has increased by 135% and 218% among high school and middle school students, respectively, in the last two years alone (Cullen et al., 2018; 2019). Due to the fact that most ENDS users vape flavored nicotine products and the growing use of zero-nicotine flavored e-liquids, it raises the questions of how chemical flavorants alter nicotine addiction and if they increase abuse liability themselves. We show that one chemical flavorant and odorant of green apple, farnesene, causes reward-related behavior on its own. These results increase our understanding on how flavorants promote neurological changes and affect nicotine addiction.
Footnotes
Authors report no conflict of interest.
This work was supported by the National Institutes on Drug Abuse at the National Institutes of Health (DA040047 to B.J.H.). Research reported in this publication was supported by NIDA and FDA Center for Tobacco Products (CTP)(DA046335 to B.J.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug administration. Funding was also provided by the PhRMA Foundation (Predoctoral fellowship in Pharmacology/Toxicology to SYC) and startup funds to BJH by the Marshall University Research Corporation.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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