Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice

dc.contributor.authorAlsharari, Shakir D.
dc.contributor.authorKing, Justin R.
dc.contributor.authorNordman, Jacob C.
dc.contributor.authorMuldoon, Pretal P.
dc.contributor.authorJackson, Asti
dc.contributor.authorZhu, Andy Z. X.
dc.contributor.authorTyndale, Rachel F.
dc.contributor.authorKabbani, Nadine
dc.contributor.authorDamaj, M. Imad.
dc.description.abstractAlthough menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c.) for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.
dc.description.sponsorshipThis work was supported by National Institute on Drug Abuse grant # DA-05274 (MID), DA020830 (RFT), http://www.drugabuse.gov/; the Endowed Chair in Addiction for the Department of Psychiatry (RFT), http://www.psychiatry.utoronto.ca/endowed-chairs/; Canadian Institutes of Health Research (MOP86471 and TMH109787) (RFT), http://www.cihr-irsc.gc.ca/e/193.html; Centre for Addiction and Mental Health (CAMH) foundation (RFT), www.camh.ca; the Canada Foundation for Innovation (#20289 and #16014) (RFT), http://www.innovation.ca/; the Ontario Ministry of Research and Innovation (RFT), https://www.ontario.ca/ministry-research-innovation; and Virginia Foundation for Healthy Youth (NK), http://www.vfhy.org/. Publication of this article was funded in part by the George Mason University Libraries Open Access Publishing Fund.
dc.identifier.citationAlsharari SD, King JR, Nordman JC, Muldoon PP, Jackson A, Zhu AZX, et al. (2015) Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice. PLoS ONE 10(9): e0137070. doi:10.1371/journal.pone.0137070
dc.publisherPublic Library of Science
dc.subjectNicotine addiction
dc.subjectBlood plasma
dc.titleEffects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice


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