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AbstractBackgroundThe use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion.MethodsAdult male C57BL/6J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine.ResultsMice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone.ConclusionsOur data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone.HighlightsFruit flavor, but not tobacco flavor, enhances e-liquid consumption and preferenceThe nicotine-free flavored e-liquid is not preferred over nicotine aloneConditioning rewarding and aversive effects are equal between nicotine and e-liquid

Alcohol and tobacco are the most commonly used addictive substances, with high comorbidity rates between alcohol use disorder and tobacco use disorder. Risk for alcohol and nicotine addiction is highly heritable, and they share common genetic factors. A GWAS in over 1 million individuals has revealed 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use. Three novel genes—SLC39A8, GRK4 and HGFAC—within loci associated with altered alcoholic drinks per week (ADW) or cigarettes per day (CPD) were selected to further study their role in alcohol and tobacco use disorder. The role of these genes was assessed using the two-bottle choice addiction paradigm in transgenic mice for each of the genes. We found significant decreases in chronic alcohol consumption and preference in female Hgfac knockout (KO) mice, and decreased nicotine preference in male Hgfac KO compared with wild-type (WT) mice. Additionally, male Slc39a8 hypomorph mice showed greater overall nicotine preference compared with WT mice, while no differences were detected for Grk4 KO mice in alcohol or nicotine consumption and preference in either sex. Thus, this study implicates Hgfac and Slc39a8 in alcohol and tobacco use in a sex-specific manner.