IntroductionTobacco use continues to be the leading preventable cause of premature deaths in the United States, with over 400,000 deaths per year attributed to cigarette smoking. 1 While nicotine is the primary tobacco constituent responsible for addiction, many of the other over 8,400 identified tobacco constituents, 2 including alkaloids, flavor additives, β-carbolines, and monoamine oxidase inhibitors, may also affect use and dependence. 3 Given the sparse knowledge about the in vivo pharmacology of most of these constituents, the objective of this study was to examine the effects on locomotor activity of anatabine and myosmine (two alkaloids that are present in larger quantities in tobacco products, including e-cigarettes; Etter, Zäther, and Svensson 4 ; Jacob et al. 5 ), cotinine (common tobacco constituent and a metabolite of nicotine; Jacob et al. 5 ) and nicotine (for comparison purposes). Nicotine doses (0.1-0.8 mg/kg, subcutaneous [s.c.]) were chosen based upon literature review, which showed that acute doses within this range affected locomotor activity, produced
AbstractIntroduction: While nicotine has been established as the primary addictive drug that promotes tobacco use, recent peer-reviewed studies suggest that tobacco smoke contains additional chemical constituents that may have addictive potential. Additional research is necessary to determine the addictive potential of these tobacco constituents individually and in combination with tobacco smoke condensate; however, the behaviorally effective constituent doses necessary to conduct such studies are unclear. The primary objective of this study was to conduct behavioral studies in adult rats to determine the relevant behaviorally effective doses of the tobacco constituents, cotinine, myosmine, and anatabine to be used in future studies assessing the addictive potential of these compounds. Methods: Separate groups of adult male Sprague Dawley rats were treated with vehicle, nicotine, or various doses of cotinine, mysomine, or anatabine. Effects on locomotor activity were measured in 10-min bins for 60 min. Results: Nicotine (0.8 mg/kg) produced a biphasic effect on locomotor activity, with hypoactivity during the first 10 min and hyperactivity at 40-50 min. In contrast, cotinine (0.1 mg/kg) and myosmine (10-50 mg/kg) decreased activity without a later increase. Anatabine significantly increased locomotor activity at 1 mg/kg, but decreased it at 10 mg/kg. Prominent effects on overt behavior were observed at anatabine doses of 10 mg/kg and above. Conclusion: Nicotine, cotinine, myosmine, and anatabine produced distinct time-and dose-dependent patterns of effects on locomotor activity. Results from the study will aid in the selection of relevant doses for future studies assessing the addictive potential of these non-nicotine tobacco constituents.