Introduction While the use of combustible cigarettes has decreased in many urban regions of America, the use of electronic nicotine delivery systems (ENDS) has dramatically increased. ENDS, or electronic cigarettes (e-cigarettes), differ from combustible cigarettes given that there are no restrictions on flavorant additives in e-liquids. With 95% of ENDS users vaping flavored e-liquids, it is critical to understand how flavors alter vaping-related behaviors. We have previously shown that menthol and green apple flavors enhance nicotine reward-related behavior in a mouse model and in the present study have investigated how menthol and green apple flavors alter e-Vape self-administration behavior in male mice. Methods Adult C57/BL6J male mice were used in vapor-inhalation self-administration assays. Mice were assigned vaping e-liquids (6 mg/mL nicotine with or without menthol or green apple flavor) to escalate on a fixed ratio 1 (FR1) schedule in daily 3 hr sessions to examine initiation-related behaviors. Following escalation, mice were transitioned to a FR3 and PR schedules in 3 hr sessions to examine reinforcement-related behaviors. Results Here we observed that male mice exhibited increased rates of self-administration escalation on a FR1 schedule when assigned to flavored e-liquids. Upon transition to FR3, mice continued to exhibit enhanced levels of reinforcement with flavored e-liquids. We also observed that mice self-administer zero-nicotine green apple flavored e-liquids. Conclusions These data provide additional evidence that ENDS flavors enhance vaping-related initiation and reinforcement-related behavior and promote the need to continue investigating the role ENDS flavors play in vaping-related behaviors. Implications There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our study here shows that flavors significantly enhance the acquisition and reinforcement of vaping-related behavior. This suggests that flavors in electronic nicotine delivery systems significantly increase the risk of addiction-related behaviors among users of vaping products.

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Upregulation of nAChRs and changes in excitability on VTA dopamine and GABA neurons correlates to changes in nicotine-reward related behavior.

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 because of 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 nicotinic 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 (pDA) neurons that were blocked by the nAChR antagonist, Dhb E. 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 because of changes in nAChR stoichiometry as our data suggest a shift toward high-sensitivity a4b 2 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.