, Volume 190, Issue 3, pp 269–319 | Cite as

Guidelines on nicotine dose selection for in vivo research

  • Shannon G. MattaEmail author
  • David J. Balfour
  • Neal L. Benowitz
  • R. Thomas Boyd
  • Jerry J. Buccafusco
  • Anthony R. Caggiula
  • Caroline R. Craig
  • Allan C. Collins
  • M. Imad Damaj
  • Eric C. Donny
  • Phillip S. Gardiner
  • Sharon R. Grady
  • Ulrike Heberlein
  • Sherry S. Leonard
  • Edward D. Levin
  • Ronald J. Lukas
  • Athina Markou
  • Michael J. Marks
  • Sarah E. McCallum
  • Neeraja Parameswaran
  • Kenneth A. Perkins
  • Marina R. Picciotto
  • Maryka Quik
  • Jed E. Rose
  • Adrian Rothenfluh
  • William R. Schafer
  • Ian P. Stolerman
  • Rachel F. Tyndale
  • Jeanne M. Wehner
  • Jeffrey M. Zirger



This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.


This review capitalizes on the authors’ collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.


Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.


The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose–response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.


Human Nonhuman primate Rat Mouse Drosophila C. elegans Zebrafish 



The conceptualization of this review grew out of discussions among the Nicotine Dependence Study Section members who review grant applications for the Tobacco-related Disease Research Program (TRPRP), University of California Office of the President. In addition, TRDRP supported the discussion meetings, compilation, and writing of this review. Although it is customary to acknowledge all funding sources, it simply is not feasible here, given the number of contributors to this review and the extensive, ongoing support by multiple institutions; acknowledgement of specific individual support is provided in each author’s primary papers in the references. Finally, with the exception of the first author/editor, authorship is listed alphabetically.


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Shannon G. Matta
    • 1
    Email author
  • David J. Balfour
    • 2
  • Neal L. Benowitz
    • 3
  • R. Thomas Boyd
    • 4
  • Jerry J. Buccafusco
    • 5
  • Anthony R. Caggiula
    • 6
  • Caroline R. Craig
    • 7
  • Allan C. Collins
    • 8
  • M. Imad Damaj
    • 9
  • Eric C. Donny
    • 6
  • Phillip S. Gardiner
    • 10
  • Sharon R. Grady
    • 8
  • Ulrike Heberlein
    • 11
  • Sherry S. Leonard
    • 12
  • Edward D. Levin
    • 13
  • Ronald J. Lukas
    • 14
  • Athina Markou
    • 15
  • Michael J. Marks
    • 8
  • Sarah E. McCallum
    • 16
  • Neeraja Parameswaran
    • 16
  • Kenneth A. Perkins
    • 17
  • Marina R. Picciotto
    • 18
  • Maryka Quik
    • 16
  • Jed E. Rose
    • 19
  • Adrian Rothenfluh
    • 11
  • William R. Schafer
    • 7
  • Ian P. Stolerman
    • 20
  • Rachel F. Tyndale
    • 21
  • Jeanne M. Wehner
    • 8
  • Jeffrey M. Zirger
    • 4
  1. 1.Department of Pharmacology, College of MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Pharmacology and NeuroscienceUniversity of Dundee Medical SchoolDundeeUK
  3. 3.Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Biopharmaceutical SciencesUniversity of California-San FranciscoSan FranciscoUSA
  4. 4.Department of Neuroscience, College of Medicine and Public HealthOhio State UniversityColumbusUSA
  5. 5.Department of PharmacologyMedical College of GeorgiaAugustaUSA
  6. 6.Department of PsychologyUniversity of PittsburghPittsburghUSA
  7. 7.Section of NeurobiologyUniversity of California-San DiegoSan DiegoUSA
  8. 8.Institute for Behavioral GeneticsUniversity of ColoradoBoulderUSA
  9. 9.Department of Pharmacology and Toxicology, Medical College of VirginiaVirginia Commonwealth UniversityRichmondUSA
  10. 10.Tobacco-Related Disease Research Program, Office of the PresidentUniversity of CaliforniaOaklandUSA
  11. 11.Department of AnatomyUniversity of California-San FranciscoSan FranciscoUSA
  12. 12.Departments of Psychiatry and PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA
  13. 13.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  14. 14.Division of NeurobiologyBarrow Neurological InstitutePhoenixUSA
  15. 15.Department of Psychiatry, School of MedicineUniversity of California-San DiegoLa JollaUSA
  16. 16.Parkinson’s InstituteSunnyvaleUSA
  17. 17.Department of PsychiatryUniversity of Pittsburgh School of MedicinePittsburghUSA
  18. 18.Department of PsychiatryYale University School of MedicineNew HavenUSA
  19. 19.Center for Nicotine and Smoking Cessation ResearchDuke University Medical CenterDurhamUSA
  20. 20.Section of Behavioral Pharmacology, Institute of PsychiatryKing’s CollegeLondonUK
  21. 21.Center for Addiction and Mental Health, Department of PharmacologyUniversity of TorontoTorontoCanada

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