Effects of commercial unflavored and vanilla-flavored e-liquids on nicotine intake and withdrawal

Abstract Electronic cigarette liquids (e-liquids) often contain flavors and solvents that may influence nicotine addiction. In this study, we characterized the dose-response relationship of commercial unflavored nicotine e-liquids and investigated the impact of vanilla-flavored e-liquids on nicotine vapor self-administration (VSA) and withdrawal in rats. Male adolescent Sprague Dawley rats self-administered aerosols generated from commercial e-liquids containing 0, 3, 6, or 12 mg/ml nicotine in a propylene glycol (PG) and glycerol (G) vehicle. The vehicle (0 mg/ml nicotine) supported robust VSA, indicating the reinforcing effects of PG/G vapor. 3 mg/ml nicotine did not support VSA, while both 6 and 12 mg/ml nicotine concentrations produced significant reinforcement, with 6 mg/ml yielding the most stable responding. The 6 mg/ml concentration was selected for subsequent comparisons with vanilla-flavored e-liquids. Vanilla flavor (0 mg/ml nicotine) led to maintained VSA behavior, confirming its reinforcing effects. However, the combination of vanilla and nicotine (6 mg/ml) did not alter nicotine intake or withdrawal severity, as assessed by mecamylamine-precipitated somatic signs. Blood nicotine and cotinine levels were similar between nicotine and vanilla + nicotine conditions, indicating that vanilla flavor did not affect systemic nicotine metabolism. Additionally, the PG/G vehicle induced significant somatic signs, suggesting that vapor exposure itself, independent of nicotine, contributes to these physiological responses. These findings provide critical insights into the reinforcing and physiological effects of both nicotine and non-nicotine constituents in e-cigarette aerosols, underscoring the need for future studies and regulatory strategies that consider the abuse liability of flavors and solvents, such as PG/G, particularly among adolescents. Significance Statement Flavored electronic nicotine delivery systems raise concern for promoting nicotine use in youth. Using a rat vapor self-administration model, we show nicotine produces concentration-dependent reinforcement, while vanilla flavor is reinforcing but does not enhance nicotine intake or withdrawal. Competing Interest Statement The authors have declared no competing interest. The list of nonstandard abbreviations - VSA - vapor self-administration - PG - propylene glycol - G - glycerol