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

  • Tanseli Nesil
  • Syeda Narmeen
  • Anousheh Bakhti-Suroosh
  • Wendy J. Lynch
Original Investigation



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.


Extended access Menthol Nicotine-seeking Progressive-ratio Reinstatement Self-administration 



We would like to acknowledge Rebecca Beiter and Elizabeth Gasteiger for technical assistance.

Funding information

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.


  1. Abdolahi A, Acosta G, Breslin FJ, Hemby SE, Lynch WJ (2010) Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex. Eur J Neurosci 31:733–741CrossRefGoogle Scholar
  2. Ahijevych K, Garrett BE (2010) The role of menthol in cigarettes as a reinforcer of smoking behavior. Nicotine Tob Res 12(Suppl 2):S110–S116CrossRefGoogle Scholar
  3. Ahmed TA (2015) Pharmacokinetics of drugs following IV bolus, IV infusion, and oral administration. In Ahmed TA (ed) Basic pharmacokinetic concepts and some clinical applications, 1st edn. IntechOpen, Rijeka, pp 53–95CrossRefGoogle Scholar
  4. Ai J, Taylor KM, Lisko JG, Tran H, Watson CH, Holman MR (2018) Menthol levels in cigarettes from eight manufacturers. Tob Control 27:335–336CrossRefGoogle Scholar
  5. Alsharari SD, King JR, Nordman JC, Muldoon PP, Jackson A, Zhu AZX, Tyndale RF, Kabbani N, Damaj MI (2015) Effects of menthol on nicotine pharmacokinetic, pharmacology and dependence in mice. PLoS One 10:e0137070CrossRefGoogle Scholar
  6. Anderson SJ (2011) Menthol cigarettes and smoking cessation behaviour: a review of tobacco industry documents. Tob Control 20(Suppl 2):ii49–ii56PubMedPubMedCentralGoogle Scholar
  7. Appleton S (1986) Proposal for the investigation of menthol pharmacokinetics by the intravenous, oral, and inhalationroutes. RJR interoffice Memorandum. Accessed April 2014
  8. Arnold JM, Roberts DCS (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Be 57:441–447CrossRefGoogle Scholar
  9. Ashoor A, Nordman JC, Veltri D, Yang KH, Al Kury L, Shuba Y, Mahgoub M, Howarth FC, Sadek B, Shehu A, Kabbani N, Oz M (2013a) Menthol binding and inhibition of alpha7-nicotinic acetylcholine receptors. PLoS One 8:e67674CrossRefGoogle Scholar
  10. Ashoor A, Nordman JC, Veltri D, Yang KH, Shuba Y, Al Kury L, Sadek B, Howarth FC, Shehu A, Kabbani N, Oz M (2013b) Menthol inhibits 5-HT3 receptor-mediated currents. J Pharmacol Exp Ther 347:398–409CrossRefGoogle Scholar
  11. Azagba S, Minaker LM, Sharaf MF, Hammond D, Manske S (2014) Smoking intensity and intent to continue smoking among menthol and non-menthol adolescent smokers in Canada. Cancer Causes Control 25:1093–1099CrossRefGoogle Scholar
  12. Benowitz NL, Herrera B, Jacob P, 3rd (2004) Mentholated cigarette smoking inhibits nicotine metabolism. J Pharmacol Exp Ther 310: 1208–1215CrossRefGoogle Scholar
  13. Biswas L, Harrison E, Gong Y, Avusula R, Lee J, Zhang M, Rousselle T, Lage J, Liu X (2016) Enhancing effect of menthol on nicotine self-administration in rats. Psychopharmacology 233:3417–3427CrossRefGoogle Scholar
  14. Brody AL, Mukhin AG, La Charite J, Ta K, Farahi J, Sugar CA, Mamoun MS, Vellios E, Archie M, Kozman M, Phuong J, Arlorio F, Mandelkern MA (2013) Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. Int J Neuropsychopharmacol 16:957–966CrossRefGoogle Scholar
  15. Carchman RA, Southwick MA (1990) Chemical senses research a research and development perspective. Phillip MorrisGoogle Scholar
  16. Cohen A, Soleiman MT, Talia R, Koob GF, George O, Mandyam CD (2015a) Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus. Psychopharmacology 232:453–463CrossRefGoogle Scholar
  17. Cohen A, Treweek J, Edwards S, Leão RM, Schulteis G, Koob GF, George O (2015b) Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats. Addict Biol 20(1):56–68CrossRefGoogle Scholar
  18. Courtemanche CJ, Palmer MK, Pesko MF (2017) Influence of the flavored cigarette ban on adolescent tobacco use. Am J Prev Med 52:e139–e146CrossRefGoogle Scholar
  19. Curry SH (1980) Drug disposition and pharmacokinetics. Blackwell Scientific, OxfordGoogle Scholar
  20. DeVito EE, Valentine GW, Herman AI, Jensen KP, Sofuoglu M (2016) Effect of menthol-preferring status on response to intravenous nicotine. Tob Regul Sci 2:317–328CrossRefGoogle Scholar
  21. Fagan P, Pokhrel P, Herzog TA, Pagano IS, Franke AA, Clanton MS, Alexander LA, Trinidad DR, Sakuma KL, Johnson CA, Moolchan ET (2016) Nicotine metabolism in young adult daily menthol and nonmenthol smokers. Nicotine Tob Res 18:437–446CrossRefGoogle Scholar
  22. Fait BW, Thompson DC, Mose TN, Jatlow P, Jordt SE, Picciotto MR, Mineur YS (2017) Menthol disrupts nicotine’s psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice. Behav Brain Res 334:72–77CrossRefGoogle Scholar
  23. Fan L, Balakrishna S, Jabba SV, Bonner PE, Taylor SR, Picciotto MR, Jordt SE (2016) Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism. Tob Control 25:ii50–ii54CrossRefGoogle Scholar
  24. FDA (2011) The physiological effects of menthol cigarettes. Food and Drug Administration. Chapter 3 1–12. Accessed Aug 2018
  25. Foulds J, Hooper MW, Pletcher MJ, Okuyemi KS (2010). Do smokers of menthol cigarettes find it harder to quit smoking? Nicotine Tob Res 12 Suppl 2:S102–109CrossRefGoogle Scholar
  26. Hans M, Wilhelm M, Swandulla D (2012) Menthol suppresses nicotinic acetylcholine receptor functioning in sensory neurons via allosteric modulation. Chem Senses 37:463–469CrossRefGoogle Scholar
  27. 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
  28. Heck JD (2010) A review and assessment of menthol employed as a cigarette flavoring ingredient. Food Chem Toxicol 48:S1–S38CrossRefGoogle Scholar
  29. Henderson BJ, Wall TR, Henley BM, Kim CH, Nichols WA, Moaddel R, Xiao C, Lester HA (2016) Menthol alone upregulates midbrain nAChRs, alters nAChR subtype stoichiometry, alters dopamine neuron firing frequency, and prevents nicotine reward. J Neurosci 36:2957–2974CrossRefGoogle Scholar
  30. Henderson BJ, Wall TR, Henley BM, Kim CH, McKinney S, Lester HA (2017) Menthol enhances nicotine reward-related behavior by potentiating nicotine-induced changes in nAChR function, nAChR upregulation, and DA neuron excitability. Neuropsychopharmacology 42:2285–2291CrossRefGoogle Scholar
  31. Hersey JC, Ng SW, Nonnemaker JM, Mowery P, Thomas KY, Vilsaint MC, Allen JA, Haviland ML (2006) Are menthol cigarettes a starter product for youth? Nicotine Tob Res 8:403–413CrossRefGoogle Scholar
  32. Hilario MR, Turner JR, Blendy JA (2012) Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. Neuropsychopharmacology 37:2661–2670CrossRefGoogle Scholar
  33. Klausner K (2011) Menthol cigarettes and smoking initiation: a tobacco industry perspective. Tob Control 20(Suppl 2):ii12–ii19PubMedPubMedCentralGoogle Scholar
  34. Kreslake JM, Wayne GF, Alpert HR, Koh HK, Connolly GN (2008a) Tobacco industry control of menthol in cigarettes and targeting of adolescents and young adults. Am J Public Health 98:1685–1692CrossRefGoogle Scholar
  35. Kreslake JM, Wayne GF, Connolly GN (2008b) The menthol smoker: tobacco industry research on consumer sensory perception of menthol cigarettes and its role in smoking behavior. Nicotine Tob Res 10:705–715CrossRefGoogle Scholar
  36. Lawrence D, Cadman B, Hoffman AC (2011) Sensory properties of menthol and smoking topography. Tob Induc Dis 9(Suppl 1):S3PubMedPubMedCentralGoogle Scholar
  37. Levy DT, Blackman K, Tauras J, Chaloupka FJ, Villanti AC, Niaura RS, Vallone DM, Abrams DB (2011) Quit attempts and quit rates among menthol and nonmenthol smokers in the United States. Am J Public Health 101:1241–1247CrossRefGoogle Scholar
  38. Li SM, Newman AH, Katz JL (2005) Place conditioning and locomotor effects of N-substituted, 4′,4″-difluorobenztropine analogs in rats. J Pharmacol Exp Ther 313:1223–1230CrossRefGoogle Scholar
  39. Liu X (2014) Effects of blockade of α4β2 and α7 nicotinic acetylcholine receptors on cue-induced reinstatement of nicotine-seeking behavior in rats. Int J Neuropsychopharmacol 17:105–116CrossRefGoogle Scholar
  40. Lynch WJ (2008) Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones. Psychopharmacology 197:237–246CrossRefGoogle Scholar
  41. Mustonen TK, Spencer SM, Hoskinson RA, Sachs DPL, Garvey AJ (2005) The influence of gender, race, and menthol content on tobacco exposure measures. Nicotine Tob Res 7:581–590CrossRefGoogle Scholar
  42. Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7(2):27–31CrossRefGoogle Scholar
  43. 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
  44. Ohlsson C, Engdahl C, Fak F, Andersson A, Windahl SH, Farman HH, Moverare-Skrtic S, Islander U, Sjogren K (2014) Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9:e92368CrossRefGoogle Scholar
  45. Paterson NE, Markou A (2004) Prolonged nicotine dependence associated with extended access to nicotine self-administration in rats. Psychopharmacology 173:64–72CrossRefGoogle Scholar
  46. Perkins KA, Karelitz JL (2014) Sensory reinforcement-enhancing effects of nicotine via smoking. Exp Clin Psychopharmacol 22:511–516CrossRefGoogle Scholar
  47. Pletcher MJ, Hulley BJ, Houston T, Kiefe CI, Benowitz N, Sidney S (2006) Menthol cigarettes, smoking cessation, atherosclerosis, and pulmonary function—the Coronary Artery Risk Development in Young Adults (CARDIA) study. Arch Intern Med 166:1915–1922CrossRefGoogle Scholar
  48. Rath JM, Teplitskaya L, Williams VF, Pearson JL, Vallone DM, Villanti AC (2017) Correlates of e-cigarette ad awareness and likeability in U.S. young adults. Tob Induc Dis 15:22CrossRefGoogle Scholar
  49. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661CrossRefGoogle Scholar
  50. Rodger A, Lewis TL (1979) The registry of toxic effects of chemical substances. NIOSH v2:34Google Scholar
  51. Rose JE, Behm FM, Westman EC, Johnson M (2000) Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Be 67:71–81CrossRefGoogle Scholar
  52. Sanchez V, Moore CF, Brunzell DH, Lynch WJ (2013) Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats. Psychopharmacology 227:403–411CrossRefGoogle Scholar
  53. Sanchez V, Moore CF, Brunzell DH, Lynch WJ (2014) Sex differences in the effect of wheel running on subsequent nicotine-seeking in a rat adolescent-onset self-administration model. Psychopharmacology 231:1753–1762CrossRefGoogle Scholar
  54. Sanchez V, Lycas MD, Lynch WJ, Brunzell DH (2015) Wheel running exercise attenuates vulnerability to self-administer nicotine in rats. Drug Alcohol Depend 156:193–198CrossRefGoogle Scholar
  55. Stowe ME (1976) Quarterly section research report: RJ Reynolds. Accessed April 2014
  56. 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
  57. Ton HT, Smart AE, Aguilar BL, Olson TT, Kellar KJ, Ahern GP (2015) Menthol enhances the desensitization of human alpha 3 beta 4 nicotinic acetylcholine receptors. Mol Pharmacol 88:256–264CrossRefGoogle Scholar
  58. Uhl GR, Walther D, Behm FM, Rose JE (2011) Menthol preference among smokers: association with TRPA1 variants. Nicotine Tob Res 13:1311–1315CrossRefGoogle Scholar
  59. Valentine JD, Hokanson JS, Matta SG, Sharp BM (1997) Self-administration in rats allowed unlimited access to nicotine. Psychopharmacology 133:300–304CrossRefGoogle Scholar
  60. Valentine GW, DeVito EE, Jatlow PI, Gueorguieva R, Sofuoglu M (2018) Acute effects of inhaled menthol on the rewarding effects of intravenous nicotine in smokers. J Psychopharmacol 32:986–994CrossRefGoogle Scholar
  61. Villanti AC, Giovino GA, Barker DC, Mowery PD, Sevilimedu V, Abrams DB (2012) Menthol brand switching among adolescents and young adults in the National Youth Smoking Cessation Survey. Am J Public Health 102:1310–1312CrossRefGoogle Scholar
  62. Villanti AC, Mowery PD, Delnevo CD, Niaura RS, Abrams DB, Giovino GA (2016a) Changes in the prevalence and correlates of menthol cigarette use in the USA, 2004-2014. Tob Control 25:ii14–ii20CrossRefGoogle Scholar
  63. 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
  64. Wackowski O, Delnevo CD (2007) Menthol cigarettes and indicators of tobacco dependence among adolescents. Addict Behav 32:1964–1969CrossRefGoogle Scholar
  65. Wang T, Wang B, Chen H (2014) Menthol facilitates the intravenous self-administration of nicotine in rats. Front Behav Neurosci 8:437PubMedPubMedCentralGoogle Scholar
  66. Westman EC, Behm FM, Rose JE (1996) Dissociating the nicotine and airway sensory effects of smoking. Pharmacol Biochem Be 53:309–315CrossRefGoogle Scholar
  67. WHO (2016) Banning menthol in tobacco products. Advisory note from WHO study group on tobacco regulation.;jsessionid=366B8AECC2B25DA66A444406C2B3E4A1?sequence=1. Accessed Aug 2018
  68. Wickham RJ, Nunes EJ, Hughley S, Silva P, Walton SN, Park J, Addy NA (2018) Evaluating oral flavorant effects on nicotine self-administration behavior and phasic dopamine signaling. Neuropharmacology 128:33–42CrossRefGoogle Scholar
  69. Willis DN, Liu B, Ha MA, Jordt SE, Morris JB (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J 25:4434–4444CrossRefGoogle Scholar
  70. Yingst JM, Veldheer S, Hammett E, Hrabovsky S, Foulds J (2017) Should electronic cigarette use be covered by clean indoor air laws? Tob Control 26:e16–e18CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Tanseli Nesil
    • 1
  • Syeda Narmeen
    • 1
  • Anousheh Bakhti-Suroosh
    • 1
  • Wendy J. Lynch
    • 1
    • 2
  1. 1.Department of Psychiatry and Neurobehavioral SciencesUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Psychiatry and Neurobehavioral SciencesCharlottesvilleUSA

Personalised recommendations