Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats
- 417 Downloads
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.
The present study examined the effects of menthol on the perseverance and relapse of nicotine-seeking behavior in rats.
Male Sprague-Dawley rats were trained to press a lever for intravenous nicotine self-administration (0.03 mg/kg/infusion) under a fixed-ratio five 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 transient receptor potential melastatin 8 (TRPM8) antagonist RQ-00203078 was given prior to menthol administration.
Continued administration of menthol sustained responses on the previously active and nicotine-reinforced lever in the extinction tests. The readministration of menthol after extinction reinstated active lever responses. In both the extinction and the reinstatement tests, a combination of pre-session menthol administration and cue representation 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.
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.
KeywordsConditioned stimulus Cue Discriminative stimulus Extinction Food seeking Menthol Nicotine seeking Reinstatement Self-administration TRPM8
This work was supported by the National Institute on Drug Abuse and Food and Drug Administration Center for Tobacco Products (R01DA037277 to X. Liu). The funding source had no other role other than financial support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Food and Drug Administration. The authors would like to thank Thomas Rousselle, Emily Fu, and Haley Nabors for their excellent technical assistance and Dr. Robert Brodell for his strong departmental support.
Compliance with ethical standards
The experimental protocol was performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the University of Mississippi Medical Center Institutional Animal Care and Use Committee.
- Barker DJ, Bercovicz D, Servilio LC, Simmons SJ, Ma S, Root DH, Pawlak AP, West MO (2014) Rat ultrasonic vocalizations demonstrate that the motivation to contextually reinstate cocaine-seeking behavior does not necessarily involve a hedonic response. Addict Biol 19:781–790CrossRefPubMedGoogle Scholar
- CDC (2014) Current cigarettes moking among adults-UnitedStates. Morb Mortal Wkly Rep 63:29–34Google Scholar
- CDC (2015) Current cigarette smoking among adults-United States 2005–2014. Morb Mortal Wkly Rep 64:1233–1240Google Scholar
- Cervo L, Di Clemente A, Orru A, Moro F, Cassina C, Pich EM, Corsi M, Gozzi A, Bifone A (2013) Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat. Addict Biol 18:800–811CrossRefPubMedGoogle Scholar
- Fagan P, Pohkrel P, Herzog T, Pagano I, Vallone D, Trinidad DR, Sakuma KL, Sterling K, Fryer CS, Moolchan E (2015) Comparisons of three nicotine dependence scales in a multiethnic sample of young adult menthol and non-menthol smokers. Drug Alcohol Depend 149:203–211CrossRefPubMedPubMedCentralGoogle Scholar
- Federal Trade Commission (2009) Cigarette report for 2006. Federal Trade Commision, Washington DCGoogle Scholar
- Giovino GA (2010) Patterns of and recent trends in the use of mentholated cigarettes in the United States. Federal Drug Administration, Tobacco Product Scientific Advisory Board, Silver SpringGoogle Scholar
- Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR (2006) Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296:47–55CrossRefPubMedGoogle Scholar
- Hopp R (1993) Menthol: its origin, chemistry, physiology and toxicological properties. Rec Adv Tob Sci 19:3–46Google Scholar
- Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006) Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63 erratum: 296:1355CrossRefPubMedGoogle Scholar
- Kallupi M, de Guglielmo G, Cannella N, Li HW, Calo G, Guerrini R, Ubaldi M, Renger JJ, Uebele VN, Ciccocioppo R (2013) Hypothalamic neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat. Psychopharmacology 226:347–355CrossRefPubMedGoogle Scholar
- Liu X (2010) Contribution of drug cue, priming, and stress to reinstatement of nicotine-seeking behavior in a rat model of relapse. In: Egger J, Kalb M (eds) Smoking relapse: causes, prevention, and recovery. Nova Science Publishers, New York, pp 143–163Google Scholar
- Moro F, Orru A, Marzo CM, Di Clemente A, Cervo L (2016) mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine. Addict Biol. https://doi.org/10.1111/adb.12443
- Reitzel LR, Nguyen N, Cao Y, Vidrine JI, Daza P, Mullen PD, Velasquez MM, Li Y, Cinciripini PM, Cofta-Woerpel L, Wetter DW (2011) Race/ethnicity moderates the effect of prepartum menthol cigarette use on postpartum smoking abstinence. Nicotine Tob Res 13:1305–1310CrossRefPubMedPubMedCentralGoogle Scholar
- Substance Abuse and Mental Health Services Administration (2009) Use of menthol cigarettes. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, RockvilleGoogle Scholar
- Tobacco Products Scientific Advisory Committee (2011) Menthol cigarettes and public health: review of the scientific evidence and recommendations. Food and Drug Administration, RockvilleGoogle Scholar
- USDHHS (2014) The health consequences of smoking-50 years of progress: A Report of the Surgeon General.Google Scholar
- Widholm JJ, Gass JT, Cleva RM, Olive MF (2011) The mGluR5 positive allosteric modulator CDPPB does not alter extinction or contextual reinstatement of methamphetamine-seeking behavior in rats. J Addict Res Ther 24;S1(4)Google Scholar
- World Health Organization (2015) http://apps.who.int/iris/bitstream/10665/178574/1/9789240694606_eng.pdf?ua=1