Effects of nicotine-containing and “nicotine-free” e-cigarette refill liquids on intracranial self-stimulation in rats

Andrew C. Harris, Peter Muelken, John R. Smethells, Katrina Yershova, Irina Stepanov, Thao Tran Olson, Kenneth J. Kellar, Mark G. LeSage

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Background: Animal models are needed to inform FDA regulation of electronic cigarettes (ECs) because they avoid limitations associated with human studies. We previously reported that an EC refill liquid produced less aversive/anhedonic effects at a high nicotine dose than nicotine alone as measured by elevations in intracranial self-stimulation (ICSS) thresholds, which may reflect the presence of behaviorally active non-nicotine constituents (e.g., propylene glycol) in the EC liquids. The primary objective of this study was to assess the generality of our prior ICSS findings to two additional EC liquids. We also compared effects of “nicotine-free” varieties of these EC liquids on ICSS, as well as binding affinity and/or functional activity of nicotine alone, nicotine-containing EC liquids, and “nicotine-free” EC liquids at nicotinic acetylcholine receptors (nAChRs). Methods and results: Nicotine alone and nicotine dose-equivalent concentrations of both nicotine-containing EC liquids produced similar lowering of ICSS thresholds at low to moderate nicotine doses, indicating similar reinforcement-enhancing effects. At high nicotine doses, nicotine alone elevated ICSS thresholds (a measure of anhedonia-like behavior) while the EC liquids did not. Nicotine-containing EC liquids did not differ from nicotine alone in terms of binding affinity or functional activity at nAChRs. “Nicotine-free” EC liquids did not affect ICSS, but bound with low affinity at some (e.g., α4ß2) nAChRs. Conclusions: These findings suggest that non-nicotine constituents in these EC liquids do not contribute to their reinforcement-enhancing effects. However, they may attenuate nicotine's acute aversive/anhedonic and/or toxic effects, which may moderate the abuse liability and/or toxicity of ECs.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalDrug and alcohol dependence
StatePublished - Apr 1 2018

Bibliographical note

Funding Information:
Funding for this study was provided by NIH/NCI grant U19- CA157345 (Hatsukami DH and Shields P, MPI; LeSage MG, PL), NIH/NIDA grant RO3 DA042009 (Harris, AC, PI), NIDA training grant T32 DA007097 (Smethells, JR; Molitor T, PI), the Minneapolis Medical Research Foundation (MMRF) Career Development Award (LeSage, MG, Harris, AC) and the MMRF Translational Addiction Research Program (Harris, AC). These funding institutions had no role in the study design, data collection, data analysis, interpretation of the data, manuscript preparation, or decision to submit the manuscript for publication. 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.

Funding Information:
The authors thank Danielle Burroughs, Laura Tally, Theresa Harmon, Andrew Banal, Christine Egan, Nettie Enshayan, Danielle Motz, Annika Skansberg, Mary Krueger, Zachary Haave, and Vipin Jain for their excellent technical assistance in conducting the experiments. Ki determinations and agonist/antagonist functional data for Experiments 3a and 3c were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN- 271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.

Publisher Copyright:
© 2018


  • Electronic cigarettes
  • Intracranial self-stimulation
  • Nicotine
  • Non-nicotine tobacco constituents
  • Tobacco control policy


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