Enhancing effect of menthol on nicotine self-administration in rats

Biswas, Lisa; Harrison, Erin; Gong, Yongzhen; Avusula, Ramachandram; Lee, Jonathan; Zhang, Meiyu; Rousselle, Thomas; Lage, Janice M.; Liu, Xiu

doi:10.1007/s00213-016-4391-x

Cited by 64 publications

(66 citation statements)

References 90 publications

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“…However, in rats that had self-administered nicotine but did not receive pre-session menthol administration (menthol-naive subjects), menthol administration neither reinstated nicotine-seeking behavior nor interacted with the nicotine cue. These results extended a role of menthol in directly enhancing nicotine reinforcement, as demonstrated in our previous work (Biswas et al, 2016), to an interoceptive cueing effect of menthol on nicotine-seeking behavior. In contrast, menthol did not produce a similar effect in the rats trained to self-administer food with pre-session menthol administration.…”

Section: Discussionsupporting

confidence: 89%

“…These findings suggest that menthol administration in smokers may set the occasion for nicotine intake and serve as a reminder of tobacco smoking, which would then facilitate nicotine seeking and trigger relapse. Together with other clinical and animal observations that showed that menthol may interact with nicotine to increase nicotine reinforcement (Ahijevych and Garrett, 2004; Ahijevych and Garrett, 2010; Alsharari et al, 2015; Biswas et al, 2016; Wang et al, 2014), these data indicate that menthol may significantly contribute to the initiation, progression, and relapse of tobacco smoking.…”

Section: Discussionsupporting

confidence: 68%

“…One hypothesis is that, in addition to directly enhancing the reinforcing actions of nicotine as demonstrated in our previous studies (Biswas et al, 2016), menthol in tobacco products even at a very low amount may readily acquire the properties of interoceptive cues for smoking and nicotine intake. Menthol may become an occasion-setter that is predictive of the presence of nicotine reinforcement.…”

Section: Introductionmentioning

confidence: 95%

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Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

et al. 2017

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Rationale Increasing clinical evidence suggests that menthol, a significant flavoring additive in tobacco products, may contribute to smoking and nicotine dependence. Relapse to smoking behavior presents a formidable challenge for the treatment of tobacco addiction. An unresolved issue is whether the mentholation of tobacco products precipitates relapse to tobacco use in abstinent smokers. Objectives The present study examined the effects of menthol on the perseverance and relapse of nicotine-seeking behavior in rats. Methods Male Sprague-Dawley rats were trained to press a lever for intravenous nicotine self-administration (0.03 mg/kg/infusion) under a fixed-ratio 5 schedule of reinforcement. Each nicotine infusion was signaled by the presentation of a sensory stimulus that was established as a discrete nicotine-conditioned cue. Five minutes prior to the sessions, the rats received an intraperitoneal injection of menthol (0.1 mg/kg) or vehicle. In the subsequent extinction test sessions, nicotine was unavailable with or without menthol and/or the nicotine-conditioned cue. The reinstatement tests were performed the following day after the extinction criterion was met. Menthol was also tested on food-seeking responses. In a subset of nicotine-trained rats, a TRPM8 antagonist RQ-00203078 was given prior to menthol administration. Results Continued administration of menthol sustained responses on the previously active and nicotine-reinforced lever in the extinction tests. The re-administration of menthol after extinction reinstated active lever responses. In both the extinction and reinstatement tests, a combination of pre-session menthol administration and cue re-presentation during the session produced a more robust behavioral effect than either menthol or the cue alone. No such effects of menthol was observed in food trained rats. RQ-00203078 did not change menthol effect on nicotine seeking. Conclusion These data demonstrated that menthol specifically sustained and reinstated nicotine-seeking behavior and this effect was independent of TRPM8 activity. These findings suggest that menthol in most tobacco products, even not menthol-labeled, may contribute to the perseverance of and relapse to tobacco-seeking behavior.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 95%

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Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

et al. 2017

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“…Menthol has also been shown to increase self-administration of nicotine (Biswas et al, 2016). However, we did not observe any menthol or nicotine-related differences in puffing behavior during the ad-lib period.…”

Section: Discussionmentioning

confidence: 99%

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Krishnan‐Sarin

Green

Kong

et al. 2017

Drug and Alcohol Dependence

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Background Tobacco products containing menthol are widely used by youth. We used ecigarettes to conduct an experimental evaluation of the independent and interactive effects of menthol and nicotine among youth. Procedures Pilot chemosensory experiments with fourteen e-cigarette users identified low (barely perceptible, 0.5%) and high (similar to commercial e-liquid, 3.5%) menthol concentrations. Sixty e-cigarette users were randomized to a nicotine concentration (0 mg/ml, 6 mg/ml, 12 mg/ml) and participated in 3 laboratory sessions. During each session, they received their assigned nicotine concentration, along with one of three menthol concentrations in random counterbalanced order across sessions (0, 0.5%, 3.5%), and participated in three fixed-dose, and an ad-lib, puffing period. Urinary menthol glucuronide and salivary nicotine levels validated menthol and nicotine exposure. We examined changes in e-cigarette liking/wanting and taste, coolness, stimulant effects, nicotine withdrawal and ad-lib use. Results Overall, the high concentration of menthol (3.5%) significantly increased e-cigarette liking/wanting relative to no menthol (p<0.001); there was marginal evidence of nicotine* menthol interactions (p=0.06), with an increase in liking/wanting when 3.5% menthol was combined with 12 mg/ml nicotine, but not 6 mg/ml nicotine. Importantly, both 0.5% and 3.5% menthol concentrations significantly improved taste and increased coolness. We did not observe nicotine or menthol-related changes in stimulant effects, nicotine withdrawal symptoms or ad-lib use. Conclusions Menthol, even at very low doses, alters the appeal of e-cigarettes among youth. Further, menthol enhances positive rewarding effects of high nicotine-containing e-cigarettes among youth.

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“…This approach allows evaluation of the aggregate effects of these constituents on EC abuse liability. This is important for understanding the abuse liability of ECs, because certain non-nicotine constituents in ECs (e.g., menthol, minor alkaloids) can enhance the addiction-related effects of nicotine, or can be behaviorally active themselves [2,4,13,14]. Because these models involve parenteral (e.g., i.v., s.c.) administration rather than inhalational exposure, they allow for the study of the addiction-related effects of EC constituents within the central nervous system (CNS), largely independent of their peripheral (e.g., sensory) effects.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis

Harris

Smethells

Palumbo

et al. 2020

IJERPH

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Background: Characterizing the determinants of the abuse liability of electronic cigarettes (ECs) in adolescents is needed to inform product regulation by the United States Food and Drug Administration (FDA). We recently reported that Vuse Menthol EC aerosol extract containing nicotine and a range of non-nicotine constituents (e.g., menthol, propylene glycol) had reduced aversive effects compared to nicotine alone in adolescent rats, whereas Aroma E-Juice EC aerosol extract did not. The current study used a behavioral economic approach to compare the relative abuse liability of these EC extracts and nicotine alone in an i.v. self-administration (SA) model in adolescents. Methods: Adolescents were tested for the SA of EC extracts prepared using an ethanol (ETOH) solvent or nicotine and saline, with and without 4% ETOH (i.e., the same concentration in the EC extracts) in 23 h/day sessions. Results. Although acquisition of SA was faster for nicotine + ETOH compared to all other formulations, the elasticity of demand for all nicotine-containing formulations was similar. Conclusions: EC aerosol extracts did not have greater abuse liability than nicotine alone in adolescents. These data suggest that nicotine may be the primary determinant of the abuse liability of these ECs in youth, at least in terms of the primary reinforcing effects of ECs mediated within the central nervous system.

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Enhancing effect of menthol on nicotine self-administration in rats

Cited by 64 publications

References 90 publications

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis

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