Delivery of nicotine in an extract of a smokeless tobacco product reduces its reinforcement-attenuating and discriminative stimulus effects in rats

Andrew C. Harris, Irina Stepanov, Paul R. Pentel, Mark G. LeSage

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Rationale Animal models of tobacco addiction rely on administration of nicotine alone or nicotine combined with isolated constituents. Models using tobacco extracts derived from tobacco products and containing a range of tobacco constituents might more accurately simulate tobacco exposure in humans. Objective To compare the effects of nicotine alone and an aqueous smokeless tobacco extract in several addiction-related animal behavioral models. Methods Nicotine alone and nicotine dose-equivalent concentrations of extract were compared in terms of their acute effects on intracranial self-stimulation (ICSS) thresholds, discriminative stimulus effects, and effects on locomotor activity. Results Similar levels of nicotine and minor alkaloids were achieved using either artificial saliva or saline for extraction, supporting the clinical relevance of the saline extracts used in these studies. Extract produced reinforcement- enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, but reduced reinforcement-attenuating (ICSS threshold-increasing) effects at a high nicotine dose. In rats trained to discriminate nicotine alone from saline, intermediate extract doses did not substitute for the training dose as well as nicotine alone. Locomotor stimulant effects and nicotine distribution to brain were similar following administration of extract or nicotine alone. Conclusions The reinforcement-attenuating and discriminative stimulus effects of nicotine delivered in an extract of a commercial smokeless tobacco product differed from those of nicotine alone. Extracts of tobacco products may be useful for evaluating the abuse liability of those products and understanding the role of non-nicotine constituents in tobacco addiction.

Original languageEnglish (US)
Pages (from-to)565-576
Number of pages12
Issue number3
StatePublished - Apr 2012

Bibliographical note

Funding Information:
Acknowledgements This study was supported by the Minneapolis Medical Research Foundation (MMRF) Translational Addiction Research Program (Harris PI), an MMRF Career Development Award (#7572, LeSage PI), and DA026444 (NIDA, LeSage PI). The authors would like to thank Dr. Steven Hecht for providing the alkaloid assay, and Drs. Hecht and Dorothy Hatsukami for helpful discussion during the early stages of this work. We would also like to thank Mylissa Staley, David Shelley, Christina Mattson, Daniel Tran, and Aleksandar Knezevich for technical assistance. No conflicts of interest.


  • Extract
  • Intracranial self-stimulation
  • Locomotor sensitization
  • Nicotine
  • Nicotine discrimination
  • Non-nicotine tobacco constituents
  • Smokeless tobacco


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