Background: Preclinical models are needed to inform regulation of tobacco products by the Food and Drug Administration (FDA). Typically, animal models of tobacco addiction involve exposure to nicotine alone or nicotine combined with isolated tobacco constituents (e.g. minor alkaloids). The goal of this study was to develop a model using extracts derived from tobacco products that contain a range of tobacco constituents to more closely model product exposure in humans. Methods: This study compared the addiction-related effects of nicotine alone and nicotine dose-equivalent concentrations of aqueous smokeless tobacco extracts on intracranial self-stimulation (ICSS) in rats. Extracts were prepared from Kodiak Wintergreen, a conventional product, or Camel Snus, a potential "modified risk tobacco product". Binding affinities of nicotine alone and extracts at various nicotinic acetylcholine receptor (nAChR) subtypes were also compared. Results: Kodiak and Camel Snus extracts contained levels of minor alkaloids within the range of those shown to enhance nicotine's behavioral effects when studied in isolation. Nonetheless, acute injection of both extracts produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, as well as similar reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high nicotine doses. Extracts and nicotine alone also had similar binding affinity at all nAChRs studied. Conclusions: Relative nicotine content is the primary pharmacological determinant of the abuse liability of Kodiak and Camel Snus as measured using ICSS. These models may be useful to compare the relative abuse liability of other tobacco products and to model FDA-mandated changes in product performance standards.
Bibliographical noteFunding Information:
The authors would like to thank Danielle Burroughs for technical assistance. Ki determinations 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. For experimental details please refer to the PDSP web site http://pdsp.med.unc.edu/and click on “Binding Assay” on the menu bar.
This work was supported by NCI U19-CA157345 (Hatsukami, DK and Shields, PG, Co-PI; LeSage, PL), the Minneapolis Medical Research Foundation (MMRF) Translational Addiction Research Program (Harris, PI), and the University of Minnesota Undergraduate Research Opportunity Program (UROP, Schmidt, Muelken, PI). The NIH , Minneapolis Medical Research Foundation, and University of Minnesota had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
- Intracranial self-stimulation
- Non-nicotine tobacco constituents
- Smokeless tobacco