Abstract
The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4β2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and β2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.
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The authors thank Michael Arends for proofreading the manuscript.
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MKa and OG designed the vapor self-administration experiment. GdG and MKl built the vapor self-administration chambers. LCS, SS, and LT performed the self-administration experiments. LCS, NV, and LT performed the behavioral experiments. LCS, GdG, JB, and YS harvested the organs. XS designed the pulmonary dysfunction experiment. AJ performed the tissue analysis. KS performed the receptor subunit experiments. LCS, LLGC, and MKa analyzed the data. LCS generated the figures. LCS prepared the manuscript and Supplementary Material. MKa and OG edited the manuscript and Supplementary Material. All of the authors reviewed the final version of the manuscript.
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Smith, L.C., Kallupi, M., Tieu, L. et al. Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use. Neuropsychopharmacol. 45, 1909–1919 (2020). https://doi.org/10.1038/s41386-020-0734-8
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DOI: https://doi.org/10.1038/s41386-020-0734-8
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