Skip to main content

Nicotinic effects of tobacco smoke constituents in nonhuman primates



Recent studies in rodents suggest that non-nicotine constituents of tobacco smoke (e.g., minor tobacco alkaloids) may promote tobacco consumption—either through their own pharmacological effects or by augmenting the effects of nicotine. However, there is scant information on the behavioral pharmacology of minor tobacco alkaloids in primate species.


The present studies were conducted to determine whether the minor tobacco alkaloids nornicotine, anabasine, anatabine, myosmine, and cotinine exhibit nicotine-like behavioral effects in squirrel monkeys.


Initial experiments were conducted to determine the effects of nicotine (0.032–1.0 mg/kg) and the minor tobacco alkaloids nornicotine (1–1.8 mg/kg), anabasine (0.1–1.0 mg/kg), anatabine (10–32 mg/kg), myosmine (0.32–1.8 mg/kg), and cotinine (10–180 mg/kg) on food-maintained performance (n = 4). Next, the ability of tobacco alkaloids to substitute for the α4β2-selective nicotinic agonist (+)-epibatidine in drug discrimination experiments was evaluated in a separate group of monkeys (n = 4).


Results show that nicotine and each minor tobacco alkaloid except cotinine (a) produced dose-related decreases in food-maintained responding; (b) substituted for (+)-epibatidine and, in additional experiments, produced additive effects when combined with nicotine; (c) induced emesis or tremor at doses that reduced food-maintained responding and had (+)-epibatidine-like discriminative-stimulus effects; and (d) based on correlation with reported receptor binding affinities, likely produced their behavioral effects through α4β2 receptor mechanisms.


Selected minor tobacco alkaloids have nicotinic-like effects that may contribute to tobacco consumption and addiction.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4



Analysis of variance


Fixed ratio




  • Anderson DJ, Arneric SP (1994) Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain. Eur J Pharmacol 253:261–267

    CAS  Article  PubMed  Google Scholar 

  • Badio B, Daly JW (1994) Epibatidine, a potent analgetic and nicotinic agonist. Mol Pharmacol 45:563–569

    CAS  PubMed  Google Scholar 

  • Bardo MT, Bevins RA, Klebaur JE, Crooks PA, Dwoskin LP (1997) (-)-Nornicotine partially substitutes for (+)-amphetamine in a drug discrimination paradigm in rats. Pharmacol, Biochem Behav 58:1083–1087

    CAS  Article  Google Scholar 

  • Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered intravenously by rats. Psychopharmacology (Berl) 146:290–296

    CAS  Article  Google Scholar 

  • Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Benowitz NL, Henningfield JE (1994) Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 331(2):123–125

    CAS  Article  PubMed  Google Scholar 

  • Benowitz NL, Henningfield JE (2013) Reducing the nicotine content to make cigarettes less addictive. Tob Control. May; 22 Suppl 1:i14-7. doi: 10.1136/tobaccocontrol-2012-050860

  • Benowitz NL, Kuyt F, Jacob P III, Jones RT, Osman AL (1983) Cotinine disposition and effects. Clin Pharmacol Ther 34(5):604–611

    CAS  Article  PubMed  Google Scholar 

  • Benowitz NL, Hukkanen J, Jacob P III (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 192:29–60

    CAS  Article  PubMed  Google Scholar 

  • Caine SB, Collins GT, Thomsen M, Wright C, Lanier RK, Mello NK (2014) Nicotine-like behavioral effects of minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents. Exp Clin Psychopharmacol 22(1):9–22

    CAS  Article  PubMed  Google Scholar 

  • Damaj MI, Creasy KR, Grove AD, Rosecrans JA, Martin BR (1994) Pharmacological effects of epibatidine optical enantiomers. Brain Res 664:34–40

    CAS  Article  PubMed  Google Scholar 

  • Decker MW, Brioni JD, Bannon AW, Arneric SP (1995) Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics. Life Sci 56:545–570

    CAS  Article  PubMed  Google Scholar 

  • Desai RI, Bergman J (2010) Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J Pharmacol Exp Ther 335(3):807–816

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Desai RI, Bergman J (2014) Methamphetamine-like discriminative-stimulus effects of nicotinic agonists. J Pharmacol Exp Ther 348(3):478–488

    Article  PubMed  PubMed Central  Google Scholar 

  • Desai RI, Bergman J (2015) Effects of nanoparticle-based vaccine, SEL-068, on nicotine discrimination in squirrel monkeys. Neuropsychopharmacology 40(9):2207–2216

    CAS  Article  PubMed  Google Scholar 

  • Desai RI, Barber DJ, Terry P (1999) Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine. Behav Pharmacol 10:647–656

    CAS  Article  PubMed  Google Scholar 

  • Desai RI, Barber DJ, Terry P (2003) Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology (Berl) 167:335–343

    CAS  Google Scholar 

  • Donny EC, Hatsukami DK, Benowitz NL, Sved AF, Tidey JW, Cassidy RN (2014) Reduced nicotine product standards for combustible tobacco: building an empirical basis for effective regulation. Prev Med 68:17–22

    Article  PubMed  Google Scholar 

  • Ferretti G, Dukat M, Giannella M, Piergentili A, Pigini M, Quaglia W, Damaj MI, Martin BR, Glennon RA (2003) Binding of nicotine and homoazanicotine analogues at neuronal nicotinic acetylcholinergic (nACh) receptors. Bioorg Med Chem Lett 13(4):733–735

    CAS  Article  PubMed  Google Scholar 

  • Goldberg SR, Risner ME, Stolerman IP, Reavill C, Garcha HS (1989) Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats. Psychopharmacology (Berl) 97(3):295–302

    CAS  Article  Google Scholar 

  • Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP (2003) Attentional effects of nicotinic agonists in rats. Neuropharmacology 44:1054–1067

    CAS  Article  PubMed  Google Scholar 

  • Harris AC, Tally L, Muelken P, Nanal A, Schmidt CE, Cao Q, LeSage MG (2015) Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats. Drug Alcohol Depend Aug 1;153:330-4. doi:10.1016/j.drugalcdep.2015.06.005

  • Hatsukami DK, Perkins KA, Lesage MG, Ashley DL, Henningfield JE, Benowitz NL, Backinger CL, Zeller M (2010) Nicotine reduction revisited: science and future directions. Tob Control 19(5):e1–e10

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoffman AC, Evans SE (2013) Abuse potential of non-nicotine tobacco smoke components: acetaldehyde, nornicotine, cotinine, and anabasine. Nicotine Tob Res 15(3):622–632

    CAS  Article  PubMed  Google Scholar 

  • Jensen AA, Mikkelsen I, Frolund B, Brauner-Osborne H, Falch E, Krogsgaard-Larsen P (2003) Carbamoylcholine homologs: novel and potent agonists at neuronal nicotinic acetylcholine receptors. Mol Pharmacol 64:865–875

    CAS  Article  PubMed  Google Scholar 

  • Kem WR, Mahnir VM, Papke RL, Lingle CJ (1997) Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors. J Pharmacol Exp Ther 283:979–992

    CAS  PubMed  Google Scholar 

  • Marks MJ, Stitzel JA, Romm E, Wehner JM, Collins AC (1986) Nicotinic binding sites in rat and mouse brain: comparison of acetylcholine, nicotine, and alpha-bungarotoxin. Mol Pharmacol 30:427–436

    CAS  PubMed  Google Scholar 

  • Marks MJ, Robinson SF, Collins AC (1996) Nicotinic agonists differ in activation and desensitization of 86Rb+ efflux from mouse thalamic synaptosomes. J Pharmacol Exp Ther 277:1383–1396

    CAS  PubMed  Google Scholar 

  • National Research Council (2011) Guide for the care and use of laboratory animals (eighth edition). The National Academies Press, Washington

    Google Scholar 

  • Reavill C, Spivak CE, Stolerman IP, Waters JA (1987) Isoarecolone can inhibit nicotine binding and produce nicotine-like discriminative-stimulus effects in rats. Neuropharmacology 26:789–792

    CAS  Article  PubMed  Google Scholar 

  • Reavill C, Jenner P, Kumar R, Stolerman IP (1988) High affinity binding of [3H] (-)-nicotine to rat brain membranes and its inhibition by analogues of nicotine. Neuropharmacology 27:235–241

    CAS  Article  PubMed  Google Scholar 

  • Risner ME, Goldberg SR, Prada JA, Cone EJ (1985) Effects of nicotine, cocaine and some of their metabolites on schedule-controlled responding by beagle dogs and squirrel monkeys. J Pharmacol Exp Ther 234(1):113–119

    CAS  PubMed  Google Scholar 

  • Rollema H, Shrikhande A, Ward KM, Tingley FD III, Coe JW, O'Neill BT, Tseng E, Wang EQ, Mather RJ, Hurst RS, Williams KE, de Vries M, Cremers T, Bertrand S, Bertrand D (2010) Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence. Br J Pharmacol 160:334–345

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Smith JW and Stolerman IP (2009) Recognising nicotine: the neurobiological basis of nicotine discrimination. Handb. Exp. Pharmaco. 192:295-333

  • Snedecor GW, Cochran WG (1967) Statistical methods, 6th edn. Iowa State University Press, Ames, Iowa

    Google Scholar 

  • Spealman RD, Goldberg SR, Gardner ML (1981) Behavioral effects of nicotine: schedule-controlled responding by squirrel monkeys. J Pharmacol Exp Ther 216:484–491

    CAS  PubMed  Google Scholar 

  • Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl) 117:2–10

    CAS  Article  Google Scholar 

  • Stolerman IP, Garcha HS, Mirza NR (1995) Dissociations between the locomotor stimulant and depressant effects of nicotinic agonists in rats. Psychopharmacology (Berl) 117:430–437

    CAS  Article  Google Scholar 

  • Stolerman IP, Chandler CJ, Garcha HS, Newton JM (1997) Selective antagonism of behavioural effects of nicotine by dihydro-beta-erythroidine in rats. Psychopharmacology (Berl) 129:390–397

    CAS  Article  Google Scholar 

  • Takada K, Swedberg MD, Goldberg SR, Katz JL (1989) Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys. Psychopharmacology (Berl) 99(2):208–212

    CAS  Article  Google Scholar 

  • Vainio PJ, Tuominen RK (2001) Cotinine binding to nicotinic acetylcholine receptors in bovine chromaffin cell and rat brain membranes. Nicotine Tob Res 3(2):177–182

    CAS  Article  PubMed  Google Scholar 

  • Vierck CJ, Hansson PT, Yezierski RP (2008) Clinical and pre-clinical pain assessment: are we measuring the same thing? Pain 135:7–10

    CAS  Article  PubMed  Google Scholar 

  • Wiley JL, Marusich JA, Thomas BF, Jackson KJ (2015) Determination of behaviorally effective tobacco constituent doses in rats. Nicotine Tob Res 17(3):368–371. doi:10.1093/ntr/ntu194

    Article  PubMed  Google Scholar 

  • Xiao Y, Kellar KJ (2004) The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells. J Pharmacol Exp Ther 310:98–107

    CAS  Article  PubMed  Google Scholar 

  • Xiao Y, Meyer EL, Thompson JM, Surin A, Wroblewski J, Kellar KJ (1998) Rat alpha3/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function. Mol Pharmacol 54(2):322–333

    CAS  PubMed  Google Scholar 

Download references


We thank Dr. Roger Spealman for his comments on an earlier version of this manuscript.

Role of funding source

This work was supported by NIH/NIDA grant DA031231. The funding source had no further role in study design, collection of data, analysis of data, interpretation of data, writing, and submission of report for publication. The authors declare that, except for income received from our primary employer and, for JB, from LWW for editorial duties, no other financial support or compensation has been received from any individual or corporate entity over the past 3 years research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Conflict of interest

The authors declare that they have no competing interests.

Authorship contributions

R.I. Desai and J Bergman participated in research design for behavioral experiments. R.I. Desai, M.R. Doyle, and S.L. Withey conducted the experiment. R.I. Desai, M.R. Doyle, and S.L. Withey performed behavioral data analysis. R.I. Desai and J. Bergman wrote or contributed to the writing of the manuscript. R.I. Desai acquired funding for the research.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Rajeev I. Desai.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Desai, R.I., Doyle, M.R., Withey, S.L. et al. Nicotinic effects of tobacco smoke constituents in nonhuman primates. Psychopharmacology 233, 1779–1789 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Nicotine
  • Minor tobacco alkaloids
  • Drug discrimination
  • Food-maintained behavior
  • Nonhuman primates
  • Nornicotine
  • Anabasine
  • Anatabine
  • Myosmine
  • Epibatidine