Determining the impact of synthetic coolants on abuse liability and initiation-related behaviors - Project Summary/Abstract Menthol has been a popular flavor of nicotine-containing products. This, at least in part, is due to its ability to enhance nicotine’s actions that contribute to addiction-related behaviors. As bans are being imple- mented to limit or restrict menthol in nicotine-containing products, non-menthol synthetic coolants are increas- ingly used in vaping products. Some of these synthetic coolants exhibit chemical structures similar to menthol and this highlights the critical need to understand the impact of synthetic coolants on nicotine’s abuse liability and their impact on initiation-related behaviors. If their impact remains unknown, regulatory authorities may never understand their risk to addiction-related behaviors and overall public health. Thus, until this knowledge gap is closed, we face the risk of increased smoking initiation, decreased cessation, and a cumulative effect of a growing population of lifelong vapers in America as the use of synthetic coolants increases. Our overall goal is to determine the impact of synthetic coolants on nicotine’s abuse liability and initiation-related behaviors. To address this, we will utilize a novel vapor self-administration assay that will provide high translational value. We hypothesize that directly linking self-administration behavior to biomarkers of nicotine abuse liability (nAChR upregulation and changes in neurophysiology) will determine the specific impact of synthetic coolants on key aspects of vaping-related behavior. Therefore, this will provide a scientific foundation for future regulatory ac- tions that target synthetic coolants. The rationale behind this comes from the applicant’s previous experience in characterizing the impact of menthol on nicotine’s abuse liability and preliminary investigations into synthetic coolants impact on nicotine reinforcement-related behavior. We will identify synthetic coolant-specific changes in nicotine’s abuse liability with three specific aims. First, we will utilize e-Vape nicotine self-administration as- says in mice to examine initiation and nicotine reinforcement in the absence and presence of synthetic cool- ants. Second, we will use the brains from the first aim to examine nAChR upregulation as a biomarker for nico- tine abuse liability and provide a direct link between self-administration behavior and nAChR upregulation. Third, we will examine changes in neurophysiology via electrophysiology and fiber photometry. This approach is innovative, in the applicant's opinion, because it establishes a direct correlation be- tween vaping-related self-administration and nAChR upregulation as well as changes in neurophysiology in an in vivo model and utilizes the exact same ENDS and e-liquids popular with human adolescent vapers. This is complemented by the use of a novel mouse expressing α4-mCherry and α6-GFP nAChR subunits that allow analysis of upregulation without the use of antibodies. The proposed research is significant, because it will es- tablish a scientific foundation to propose future regulations regarding synthetic coolants to improve public health.
