Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration

Abstract

Rationale: Epidemiological data suggest that menthol may increase vulnerability to cigarette/ nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine.Objective: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure.Methods: Following acquisition, adolescent rats were given 23-hr/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10-days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive-ratio responding for nicotine (0.01 mg/kg/infusion).Results: Menthol decreased PR responding for nicotine, but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas, the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish. Conclusions:Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals.

Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex

“…To address behavioral differences in Experiment 1, we compared the number of infusions obtained over the 10-day extended access self-administration period between the five groups later tested under sedentary or exercise conditions using repeated measures ANOVA. Posthoc comparisons to controls (saline, cocaine sedentary) were made using Dunnett's ttests (Nesil et al 2018;Ohlsson et al 2014), and comparisons of the first and last session were made using a paired t-test. These same analyses were also used to compare daily distance run during the first seven exercise sessions, and the number of formerly-active lever responses during the first 6 extinction sessions and during the last extinction session versus the reinstatement session.…”

Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine‐seeking following extended access self‐administration

“…Univariate ANOVA was used to analyze the group differences in active‐lever responding during extinction and, as a measure of total nicotine‐seeking, active‐lever responding during both extinction and reinstatement. Post hoc comparison to controls (saline sedentary and nicotine sedentary) was made using Dunnett's one‐tailed (for predicted differences in extinction responding) t tests (Nesil, Narmeen, Bakhti‐Suroosh, & Lynch, ; Ohlsson et al., ).…”

Review of industry reports on EU priority tobacco additives part A: Main outcomes and conclusions

“…However, another study showed that menthol did not change dopamine release or nicotine self-administration, but did reverse oral nicotine taste aversion in a two-bottle choice test 38 . Besides, Nesil et al 39 concluded from a study in rats that ‘pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine’s reinforcing effects and some measures of relapse vulnerability’.…”

“…Altogether, a large body of independent literature, except for Nesil et al 39 , supports an intricate interaction between nicotine and menthol, which increases the addictiveness and/or attractiveness of tobacco. This seems consistent with the conclusions by the FDA TPSAC in the comprehensive 2011 report on menthol 40 , stating that there is sufficient evidence to indicate that those who smoke menthol-containing products tend to be more dependent.…”