Menthol disrupts nicotine’s psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice

Abstract

Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol’s influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted.

Comparative Indoor Pollution from Glo, Iqos, and Juul, Using Traditional Combustion Cigarettes as Benchmark: Evidence from the Randomized SUR-VAPES AIR Trial

“…Furthermore, building upon accruing evidence suggesting the impact of different flavors of a given MRP on its risk profile, we explored within-device (i.e., between-flavor) polluting effects, finding indeed that some flavors are associated with more indoor pollution than others [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Notwithstanding the evident impact of smoker features (which may range from habitus to cardiopulmonary physiology or smoking style), it is clear that MRP should not be considered all identical, and even specific flavors may be more or less hazardous than others [ 38 , 41 ]. Indeed, differences in exhaled aerosols from different smokers depend on many factors, including individual characteristics (i.e., age, gender, lung capacity) and status (stress, anxiety, time since the last cigarette, nicotine addiction degree, etc.…”

Comparing taste preference for menthol stereoisomers in adolescent Sprague–Dawley rats.

“…From P33 to P41, rats were given a choice between water and escalating doses of menthol (0, 10, 50, and 100 mg/L), with the dose escalating every 2 days. The doses selected in these studies are similar to other preclinical rat and mouse studies (Bagdas et al, 2020;Fait et al, 2017;Fan et al, 2016;Wickham et al, 2018), and at concentrations comparable to those seen in oral tobacco products (Celebucki et al, 2005;Fan et al, 2016). To avoid potential side biases, the bottle locations were alternated daily, with food placement equidistant from each bottle (Nesil et al, 2011;Yoneyama et al, 2008).…”

“…Preclinical studies support the epidemiological evidence that menthol exacerbates tobacco smoking (Wickham, 2019). Indeed, preclinical studies have demonstrated that adding menthol to a nicotine solution, which is bitter, increases oral nicotine consumption in mice (Fait et al, 2017; Fan et al, 2016) and rats (Bagdas et al, 2020; Wickham et al, 2018). Moreover, menthol can reduce respiratory irritation responses to smoke irritants (Willis et al, 2011).…”

Cotinine inhibits TLR4/NF-κB signaling pathway and improves deep vein thrombosis in rats

“…Cotinine, with chemical formula C 10 H 12 N 2 O and a molecular weight of 176.22, can stimulate the nervous system [11]. It is the primary metabolite of nicotine in vivo, mainly present in blood and excreted via urine.…”