Project Summary/Abstract: Characterizing flavors in tobacco products are associated with increased tobacco use initiation, reinforcement, and difficulty quitting. In addition to characterizing flavors, tobacco products contain odorless sensory additives such as sweeteners and synthetic cooling agents found in e-cigarettes and smokeless tobacco products. Because these chemicals are odorless, they may not be considered characterizing flavors under current FDA definitions and may continue to be added to tobacco products even when characterizing flavors are banned. Solvent/humectant composition of e-cigarettes and smokeless tobacco, with different combinations of propylene glycol and glycerol, and different levels of irritancy and sweetness, may also affect product perceptions. Moreover, certain forms of recently introduced synthetic nicotine may also affect the sensory properties of tobacco products and alter nicotine use behaviors. The effects of these odorless constituents (sweeteners, synthetic cooling agents, solvents, and synthetic nicotine) on youth and adult tobacco product use, especially in the critical context of transition from intermittent adolescent use to persistent adult tobacco use, remain poorly understood. We propose to determine how these odorless constituents alter the sensory and addictive properties of nicotine at different ages, and how early intermittent exposure to products containing these constituents alters nicotine use behaviors in adulthood. Specifically, we will assess the effects of odorless constituents on sensory and addictive properties of nicotine in adolescent and adult rodents (Aim 1). We will use rodent taste reactivity and respiratory exposure assays to determine whether sweeteners, cooling agents, and solvents modulate oral and respiratory sensory responses to tobacco-derived and synthetic nicotine stereoisomers. We will also examine the effects of synthetic cooling agents on nicotine use behaviors (initiation, maintenance, withdrawal, reinstatement) and nicotine-induced dopamine release in brain (brain reward system). We will evaluate interactive effects of cooling agents, solvent ratios, and nicotine enantiomers on nicotine use behaviors using operant vapor self-administration. In addition, we will examine how intermittent exposure to odorless constituents in vapor or oral nicotine in adolescent rodents affects nicotine use behaviors in adulthood (Aim 2). We will use a mixed vapor passive exposure and self-administration model as well as choice drinking assays to evaluate and compare the effects of intermittent exposure and preconditioning to sweetener and synthetic coolants or characterizing flavors during adolescence. We will determine whether exposure to these additives alters adult nicotine seeking, dependence, reward-related behaviors, and brain dopamine release later in life. Our findings will also evaluate the role of sex and age in the effects of odorless constituents on tobacco use. Project outcome...