Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration
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.
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.
Following acquisition, adolescent rats were given 23-h/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).
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.
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.
KeywordsExtended access Menthol Nicotine-seeking Progressive-ratio Reinstatement Self-administration
We would like to acknowledge Rebecca Beiter and Elizabeth Gasteiger for technical assistance.
This study was supported by the Virginia Commonwealth University’s Center for the Study of Tobacco Products Pilot Research Program, the University of Virginia’s 4-VA Innovation Grant Project (WJL), and the National Institute on Drug Abuse (R01DA024716; WJL).
Compliance with ethical standards
All procedures were conducted in accordance with the guidelines set by the University of Virginia Animal Care and Use Committee.
Conflict of interest
The authors declare that they have no conflict of interest.
- Appleton S (1986) Proposal for the investigation of menthol pharmacokinetics by the intravenous, oral, and inhalationroutes. RJR interoffice Memorandum. http://tobaccodocuments.org/product_design/506224728-4732.html. Accessed April 2014
- Carchman RA, Southwick MA (1990) Chemical senses research a research and development perspective. Phillip MorrisGoogle Scholar
- Curry SH (1980) Drug disposition and pharmacokinetics. Blackwell Scientific, OxfordGoogle Scholar
- FDA (2011) The physiological effects of menthol cigarettes. Food and Drug Administration. Chapter 3 1–12. https://www.fda.gov/downloads/ucm361598.pdf. Accessed Aug 2018
- Harrison E, Biswas L, Avusula R, Zhang M, Gong Y, Liu X (2017) Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats. In: Psychopharmacology (Berl), vol 234, pp 3443–3453Google Scholar
- O’Dell LE, Chen SA, Smith RT, Specio SE, Balster RL, Paterson NE, Markou A, Zorrilla EP, Koob GF (2007) Extended access to nicotine self-administration leads to dependence: circadian measures, withdrawal measures, and extinction behavior in rats. J Pharmacol Exp Ther 320:180–193CrossRefGoogle Scholar
- Rodger A, Lewis TL (1979) The registry of toxic effects of chemical substances. NIOSH v2:34Google Scholar
- Stowe ME (1976) Quarterly section research report: RJ Reynolds. http://legacy.library.ucsf.edu/tid/tzu68d00. Accessed April 2014
- Thompson MF, Poirier GL, Davila-Garcia MI, Huang W, Tam K, Robidoux M, Dubuke ML, Shaffer SA, Colon-Perez L, Febo M, DiFranza JR, King JA (2018) Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence. J Psychopharmacol 32:332–343CrossRefGoogle Scholar
- Villanti AC, Rath JM, Williams VF, Pearson JL, Richardson A, Abrams DB, Niaura RS, Vallone DM (2016b) Impact of exposure to electronic cigarette advertising on susceptibility and trial of electronic cigarettes and cigarettes in US young adults: a randomized controlled trial. Nicotine Tob Res 18:1331–1339CrossRefGoogle Scholar
- WHO (2016) Banning menthol in tobacco products. Advisory note from WHO study group on tobacco regulation. http://apps.who.int/iris/bitstream/handle/10665/205928/9789241510332_eng.pdf;jsessionid=366B8AECC2B25DA66A444406C2B3E4A1?sequence=1. Accessed Aug 2018