Abstract
Although 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.
Highlights
Menthol is a commonly used additive in tobacco products
Many factors have been implicated in the initiation and dependence of menthol cigarettes, earlier studies showed that menthol itself inhibits nicotine metabolism [1] and that menthol cigarette smoking leads to elevated serum nicotine and cotinine levels and greater exhaled carbon monoxide (CO) levels [2]
We tested the effect of menthol on in vivo plasma nicotine levels after administration of nicotine (2.5 mg/kg s.c.) in mice pretreated with vehicle or menthol (100 mg/kg, i.p.)
Summary
Menthol is a commonly used additive in tobacco products. In cigarettes, menthol has been shown to affect a smoker's exposure to nicotine [1], [2] and smokers who use mentholated cigarettes have lower cessation rates in standardized treatment programs than smokers who use non-menthol cigarettes [3], [4], [5]. Many factors have been implicated in the initiation and dependence of menthol cigarettes, earlier studies showed that menthol itself inhibits nicotine metabolism [1] and that menthol cigarette smoking leads to elevated serum nicotine and cotinine levels and greater exhaled carbon monoxide (CO) levels [2]. These elevated levels of nicotine may influence smoking dependence and intake since nicotine mediates most of the pharmacological and addictive properties of tobacco. In addition to sensory responses, nicotine-induced decreases in body temperature, due to cutaneous vasodilation, are significantly diminished after both chronic and acute menthol administrations [7]
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