Route of administration effects on nicotine discrimination in female and male mice

Abstract

Background: Use of electronic cigarettes (e-cigarettes) has increased exponentially since their appearance on the U.S. market around 2007. To provide preclinical models of vaping that incorporate olfactory cues and chemosensory effects (including flavors) that play a role in human vaping behavior, the feasibility of using a modified e-cigarette device for delivery of aerosolized nicotine was examined in a nicotine discrimination procedure in mice. Methods: Adult female and male C57BL/6 mice were trained to discriminate 0.75 mg/kg subcutaneous (s.c.) nicotine from saline. After determination of a s.c. nicotine dose-effect curve, aerosolized freebase nicotine and nicotine-containing tobacco products (i.e., non-flavored and Arctic Blast e-liquids) were evaluated. Results: Nicotine (s.c.) dose-dependently substituted in mice of both sexes, although females showed less sensitivity and greater variability. By contrast, aerosolized nicotine, regardless of formulation, produced concentration-dependent increases up to maximum of 46–62% nicotine-associated responding. Brain nicotine concentrations for each sex were similar for s.c. 0.75 mg/kg nicotine and 30 mg/ml freebase nicotine. Conclusions: Mice of both sexes readily acquired s.c. nicotine discrimination, but females showed less sensitivity. Further, all three formulations of aerosolized nicotine produced increases in nicotine-like responding in mice of each sex. However, the maximum magnitude of these increases did not engender a similar degree of substitution as s.c. 0.75 mg/kg nicotine, despite similar brain concentrations of nicotine at 30 mg/ml aerosolized nicotine. Additional research is needed for determination of the reason(s); however, results here demonstrate initial feasibility for examination of the discriminative stimulus effects of vaped drugs such as nicotine.