Stimulus Mediation, Specificity and Impact of Menthol in Rats Trained to Discriminate Puffs of Nicotine E-cigarette Aerosol from Nicotine-free Aerosol

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2024 Mar 23

PMID 38519818

Authors

Yasmin Alkhlaif

Keith L Shelton

Affiliations

Soon will be listed here.

Abstract

Rationale: It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question.

Objectives: Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans.

Methods: Rats were trained to discriminate between ten, 10 s puffs of aerosol generated from 3 mg/ml nicotine e-liquid and nicotine-free e-liquid using a food-reinforced operant procedure. Following acquisition, tests were conducted to determine the specificity of the nicotine aerosol stimulus as well as the impact to the stimulus effects of nicotine resulting from the addition of menthol to e-liquid.

Results: Rats learned the nicotine aerosol puff vs vehicle puff discrimination in a mean of 25 training sessions. Injected nicotine fully substituted for the stimulus effects of nicotine aerosol. The stimulus effects of nicotine aerosol were blocked by the nicotinic receptor antagonist mecamylamine. The nicotinic receptor partial agonist, varenicline as well as the stimulant d-amphetamine substituted more robustly for nicotine aerosol puffs than did the NMDA antagonist, ketamine. Menthol enhanced the stimulus effects of nicotine aerosol without altering nicotine blood plasma levels.

Conclusions: Nicotine aerosol puffs can function as a training stimulus in rats. The stimulus effects were CNS-mediated and receptor specific. Menthol appears to enhance the stimulus effects of nicotine aerosol through a pharmacodynamic rather than pharmacokinetic mechanism.

References

Kasza K, Rivard C, Seo Y, Reid J, Gravely S, Fong G . Use of Electronic Nicotine Delivery Systems or Cigarette Smoking After US Food and Drug Administration-Prioritized Enforcement Against Fruit-Flavored Cartridges. JAMA Netw Open. 2023; 6(6):e2321109. PMC: 10314301. DOI: 10.1001/jamanetworkopen.2023.21109. View

Huynh Y, Raimondi A, Schuster C, Finkner A, Selleck C, Bevins R . Investigating the interoceptive stimulus effects of injected menthol in rats. Exp Clin Psychopharmacol. 2019; 28(1):19-25. DOI: 10.1037/pha0000295. View

Duka T, Tasker R, Russell K, Stephens D . Discriminative stimulus properties of nicotine at low doses: the effects of caffeine preload. Behav Pharmacol. 1998; 9(3):219-29. View

Chance W, Murfin D, Krynock G, ROSECRANS J . A description of the nicotine stimulus and tests of its generalization to amphetamine. Psychopharmacology (Berl). 1977; 55(1):19-26. DOI: 10.1007/BF00432812. View

Biswas L, Harrison E, Gong Y, Avusula R, Lee J, Zhang M . Enhancing effect of menthol on nicotine self-administration in rats. Psychopharmacology (Berl). 2016; 233(18):3417-27. PMC: 4990499. DOI: 10.1007/s00213-016-4391-x. View

Rose J . Discriminability of nicotine in tobacco smoke: implications for titration. Addict Behav. 1984; 9(2):189-93. DOI: 10.1016/0306-4603(84)90056-x. View

Farsalinos K . Electronic cigarettes: an aid in smoking cessation, or a new health hazard?. Ther Adv Respir Dis. 2017; 12:1753465817744960. PMC: 5937152. DOI: 10.1177/1753465817744960. View

Shelton K, Nicholson K . Pharmacological classification of the abuse-related discriminative stimulus effects of trichloroethylene vapor. J Drug Alcohol Res. 2014; 3:235839. PMC: 4155754. DOI: 10.4303/jdar/235839. View

Snell L, Nicksic N, Panteli D, Burke S, Eissenberg T, Fattore G . Emerging electronic cigarette policies in European member states, Canada, and the United States. Health Policy. 2021; 125(4):425-435. PMC: 8025686. DOI: 10.1016/j.healthpol.2021.02.003. View

10.

Jasinski D, Henningfield J . Human abuse liability assessment by measurement of subjective and physiological effects. NIDA Res Monogr. 1989; 92:73-100. View

11.

Wooters T, Bevins R, Bardo M . Neuropharmacology of the interoceptive stimulus properties of nicotine. Curr Drug Abuse Rev. 2010; 2(3):243-55. PMC: 3086090. DOI: 10.2174/1874473710902030243. View

12.

Farsalinos K, Spyrou A, Tsimopoulou K, Stefopoulos C, Romagna G, Voudris V . Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci Rep. 2014; 4:4133. PMC: 3935206. DOI: 10.1038/srep04133. View

13.

Kuiper N, Gammon D, Loomis B, Falvey K, Wang T, King B . Trends in Sales of Flavored and Menthol Tobacco Products in the United States During 2011-2015. Nicotine Tob Res. 2017; 20(6):698-706. PMC: 5711620. DOI: 10.1093/ntr/ntx123. View

14.

Picciotto M, Addy N, Mineur Y, Brunzell D . It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol. 2008; 84(4):329-42. PMC: 2390914. DOI: 10.1016/j.pneurobio.2007.12.005. View

15.

Huynh Y, Raimondi A, Finkner A, Kuck J, Selleck C, Bevins R . Menthol blunts the interoceptive discriminative stimulus effects of nicotine in female but not male rats. Psychopharmacology (Berl). 2020; 237(8):2395-2404. PMC: 7354904. DOI: 10.1007/s00213-020-05542-8. View

16.

Porter J, Prus A, Overton D . Drug Discrimination: Historical Origins, Important Concepts, and Principles. Curr Top Behav Neurosci. 2018; 39:3-26. DOI: 10.1007/7854_2018_40. View

17.

Thompson M, Poirier G, Davila-Garcia M, Huang W, Tam K, Robidoux M . Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence. J Psychopharmacol. 2017; 32(3):332-343. DOI: 10.1177/0269881117719265. View

18.

Perkins K, DiMarco A, Grobe J, Scierka A, STILLER R . Nicotine discrimination in male and female smokers. Psychopharmacology (Berl). 1994; 116(4):407-13. DOI: 10.1007/BF02247470. View

19.

Garza R, Johanson C . The discriminative stimulus properties of cocaine in the rhesus monkey. Pharmacol Biochem Behav. 1983; 19(1):145-8. DOI: 10.1016/0091-3057(83)90323-4. View

20.

Preston K . Drug discrimination methods in human drug abuse liability evaluation. Br J Addict. 1991; 86(12):1587-94. DOI: 10.1111/j.1360-0443.1991.tb01752.x. View