, Volume 180, Issue 1, pp 41–48 | Cite as

Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm

  • Margaret Rukstalis
  • Christopher Jepson
  • Andrew Strasser
  • Kevin G. Lynch
  • Kenneth Perkins
  • Freda Patterson
  • Caryn Lerman
Original Investigation



Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated.


This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = “denicotinized”) cigarettes.


In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette.


The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices.


These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies.


Nicotine Smoking Naltrexone Human Opiates 


  1. Almeida LE, Pereira EF, Alkondon M, Fawcett WP, Randall WR, Albuquerque EX (2000) The opioid antagonist naltrexone inhibits activity and alters expression of alpha7 and alpha4beta2 nicotinic receptors in hippocampal neurons: implications for smoking cessation programs. Neuropharmacology 39:2740–2755Google Scholar
  2. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ, Richelson E et al (1995) Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 56:395–401PubMedGoogle Scholar
  3. Balfour DJ (2002) The neurobiology of tobacco dependence: a commentary. Respiration 69:7–11Google Scholar
  4. Boyadjieva NI, Sarkar DK (1997) The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci 61:PL59–PL66CrossRefGoogle Scholar
  5. Brauer LH, Behm FM, Westman EC, Patel P, Rose JE (1999) Naltrexone blockade of nicotine effects in cigarette smokers. Psychopharmacology (Berl) 143:339–346CrossRefGoogle Scholar
  6. Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE (2001) Individual differences in smoking reward from de-nicotinized cigarettes. Nicotine Tob Res 3:101–109CrossRefGoogle Scholar
  7. Chait LD, Burke KA (1994) Preference for high- versus low-potency marijuana. Pharmacol Biochem Behav 49:643–647CrossRefGoogle Scholar
  8. Collins BN, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, Kaufmann V, Pinto A, Hawk L, Niaura R, Epstein LH, Lerman C (2004) Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling. Nicotine Tob Res 6:27–37CrossRefGoogle Scholar
  9. Conte-Devolx B, Oliver C, Giraud P, Gillioz P, Castanas E, Lissitzky JC, Boudouresque F, Millet Y (1981) Effect of nicotine on in vivo secretion of melanocorticotropic hormones in the rat. Life Sci 28:1067–1073CrossRefGoogle Scholar
  10. Cousins MS, Stamat HM, de Wit H (2001) Acute doses of d-amphetamine and bupropion increase cigarette smoking. Psychopharmacology (Berlin) 157:243–253CrossRefGoogle Scholar
  11. Covey LS, Glassman AH, Stetner F (1999) Naltrexone effects on short-term and long-term smoking cessation. J Addict Dis 18:31–40Google Scholar
  12. Davenport KE, Houdi AA, Van Loon GR (1990) Nicotine protects against mu-opioid receptor antagonism by beta-funaltrexamine: evidence for nicotine-induced release of endogenous opioids in brain. Neurosci Lett 113:40–46CrossRefGoogle Scholar
  13. de Wit H (1996) Priming effects with drugs and other reinforcers. Exp Clin Psychopharmacol 4:5–10CrossRefGoogle Scholar
  14. de Wit H, McCracken SG (1990) Ethanol self-administration in males with and without an alcoholic first-degree relative. Alcohol Clin Exp Res 14:63–70Google Scholar
  15. Epstein AM, King AC (2004) Naltrexone attenuates acute cigarette smoking behavior. Pharmacol Biochem Behav 77:29–37CrossRefGoogle Scholar
  16. Ferris RM, Beaman OJ (1983) Bupropion: a new antidepressant drug, the mechanism of action of which is not associated with down-regulation of postsynaptic beta-adrenergic, serotonergic (5-HT2), alpha 2-adrenergic, imipramine and dopaminergic receptors in brain. Neuropharmacology 22:1257–1267Google Scholar
  17. Ferris RM, Maxwell RA, Cooper BR, Soroko FE (1982) Neurochemical and neuropharmacological investigations into the mechanisms of action of bupropion. HCl—a new atypical antidepressant agent. Adv Biochem Psychopharmacol 31:277–286Google Scholar
  18. Ferris RM, Cooper BR, Maxwell RA (1983) Studies of bupropion’s mechanism of antidepressant activity. J Clin Psychiatry 44:74–78Google Scholar
  19. Ferry L, Johnston JA (2003) Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience. Int J Clin Pract 57:224–230Google Scholar
  20. Fiore MC, Smith SS, Jorenby DE, Baker TB (1994) The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 271:1940–1947CrossRefGoogle Scholar
  21. George TP, O’Malley SS (2004) Current pharmacological treatments for nicotine dependence. Trends Pharmacol Sci 25:42–48CrossRefGoogle Scholar
  22. Gorelick DA, Rose J, Jarvik ME (1989) Effect of naloxone on cigarette smoking. J Subst Abuse 1:153–159Google Scholar
  23. Hayford KE, Patten CA, Rummans TA, Schroeder DR, Offord KP, Croghan IT, Glover ED, Sachs DP, Hurt RD (1999) Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. Br J Psychiatry 174:173–178Google Scholar
  24. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. Br J Addict 86:1119–1127PubMedGoogle Scholar
  25. Holm KJ, Spencer CM (2000) Bupropion: a review of its use in the management of smoking cessation. Drugs 59:1007–1024Google Scholar
  26. Houdi AA, Pierzchala K, Marson L, Palkovits M, Van Loon GR (1991) Nicotine-induced alteration in Tyr–Gly–Gly and Met-enkephalin in discrete brain nuclei reflects altered enkephalin neuron activity. Peptides 12:161–166CrossRefGoogle Scholar
  27. Houtsmiller EJ, Clemmey PA, Sigler LA, Stitzer ML (1997) Effects of naltrexone on smoking and abstinence. In: Harris LS (ed) Problems of drug dependence 1996: Proceedings of the 58th Annual Scientific Conference. USDHHS, Washington, DCGoogle Scholar
  28. Hughes JR, Shiffman S, Callas P, Zhang J (2003) A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tob Control 12:21–27CrossRefGoogle Scholar
  29. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM (1997) A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337:1195–1202CrossRefGoogle Scholar
  30. Hurt RD, Wolter TD, Rigotti N, Hays JT, Niaura R, Durcan MJ, Gonzales D, Sachs DP, Johnston JA, Offord KP (2002) Bupropion for pharmacologic relapse prevention to smoking: predictors of outcome. Addict Behav 27:493–507CrossRefGoogle Scholar
  31. Hutchison KE, Monti PM, Rohsenow DJ, Swift RM, Colby SM, Gnys M, Niaura RS, Sirota AD (1999) Effects of naltrexone with nicotine replacement on smoking cue reactivity: preliminary results. Psychopharmacology (Berlin) 142:139–143CrossRefGoogle Scholar
  32. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340:685–691CrossRefPubMedGoogle Scholar
  33. Karras A, Kane JM (1980) Naloxone reduces cigarette smoking. Life Sci 27:1541–1545CrossRefPubMedGoogle Scholar
  34. King AC, Meyer PJ (2000) Naltrexone alteration of acute smoking response in nicotine-dependent subjects. Pharmacol Biochem Behav 66:563–572CrossRefGoogle Scholar
  35. Kogan MJ, Verebey K, Mule SJ (1977) Estimation of the systemic availability and other pharmacokinetic parameters of naltrexone in man after acute and chronic oral administration. Res Commun Chem Pathol Pharmacol 18:29–34Google Scholar
  36. Krishnan-Sarin S, Rosen MI, O’Malley SS (1999) Naloxone challenge in smokers. Preliminary evidence of an opioid component in nicotine dependence. Arch Gen Psychiatry 56:663–668CrossRefGoogle Scholar
  37. Lee MC, Wagner HN Jr, Tanada S, Frost JJ, Bice AN, Dannals RF (1988) Duration of occupancy of opiate receptors by naltrexone. J Nucl Med 29:1207–1211PubMedGoogle Scholar
  38. Litten RZ, Allen JP (1999) Medications for alcohol, illicit drug, and tobacco dependence. An update of research findings. J Subst Abuse Treat 16:105–112CrossRefGoogle Scholar
  39. Malin DH, Lake JR, Carter VA, Cunningham JS, Wilson OB (1993) Naloxone precipitates nicotine abstinence syndrome in the rat. Psychopharmacology (Berlin) 112:339–342Google Scholar
  40. Malin DH, Lake JR, Payne MC, Short PE, Carter VA, Cunningham JS, Wilson OB (1996) Nicotine alleviation of nicotine abstinence syndrome is naloxone-reversible. Pharmacol Biochem Behav 53:81–85CrossRefGoogle Scholar
  41. Meyer MC, Straughn AB, Lo MW, Schary WL, Whitney CC (1984) Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration. J Clin Psychiatry 45:15–19Google Scholar
  42. Nemeth-Coslett R, Griffiths RR (1986) Naloxone does not affect cigarette smoking. Psychopharmacology (Berlin) 89:261–264CrossRefGoogle Scholar
  43. Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1990) In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse 6:106–112CrossRefGoogle Scholar
  44. Oliveto AH, Hughes JR, Higgins ST, Bickel WK, Pepper SL, Shea PJ, Fenwick JW (1992) Forced-choice versus free-choice procedures: caffeine self-administration in humans. Psychopharmacology (Berlin) 109:85–91Google Scholar
  45. Palmer R, Berens A (1983) Double blind study of the effect of Naloxone on the pleasure of smoking. Fed Proc 42:654Google Scholar
  46. Perkins KA, Grobe JE, Weiss D, Fonte C, Caggiula A (1996) Nicotine preference in smokers as a function of smoking abstinence. Pharmacol Biochem Behav 55:257–263CrossRefPubMedGoogle Scholar
  47. Perkins KA, Gerlach D, Broge M, Fonte C, Wilson A (2001) Reinforcing effects of nicotine as a function of smoking status. Exp Clin Psychopharmacol 9:243–250CrossRefGoogle Scholar
  48. Perkins KA, Broge M, Gerlach D, Sanders M, Grobe JE, Cherry C, Wilson AS (2002) Acute nicotine reinforcement, but not chronic tolerance, predicts withdrawal and relapse after quitting smoking. Health Psychol 21:332–339CrossRefPubMedGoogle Scholar
  49. Peters MJ, Morgan LC (2002) The pharmacotherapy of smoking cessation. Med J Aust 176:486–490Google Scholar
  50. Pickworth WB, Fant RV, Nelson RA, Rohrer MS, Henningfield JE (1999) Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine Tob Res 1:357–364Google Scholar
  51. Pierzchala K, Houdi AA, Van Loon GR (1987) Nicotine-induced alterations in brain regional concentrations of native and cryptic Met- and Leu-enkephalin. Peptides 8:1035–1043CrossRefGoogle Scholar
  52. Robinson ML, Houtsmuller EJ, Moolchan ET, Pickworth WB (2000) Placebo cigarettes in smoking research. Exp Clin Psychopharmacol 8:326–332CrossRefGoogle Scholar
  53. Rose JE, Behm FM, Westman EC, Johnson M (2000) Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav 67:71–81CrossRefPubMedGoogle Scholar
  54. Rukstalis MR, Stromberg MF, O’Brien CP, Volpicelli JR (2000) 6-beta-naltrexol reduces alcohol consumption in rats. Alcohol Clin Exp Res 24:1593–1596CrossRefGoogle Scholar
  55. Rusted JM, Graupner L, Greenwood K (1996) Methodological considerations in nicotine research: the use of “denicotinised” cigarettes as the control condition in smoking studies. Psychopharmacology (Berlin) 125:176–178Google Scholar
  56. Shahan TA, Bickel WK, Madden GJ, Badger GJ (1999) Comparing the reinforcing efficacy of nicotine containing and de-nicotinized cigarettes: a behavioral economic analysis. Psychopharmacology (Berlin) 147:210–216CrossRefGoogle Scholar
  57. Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327PubMedGoogle Scholar
  58. Sutherland G, Stapleton JA, Russell MA, Feyerabend C (1995) Naltrexone, smoking behaviour and cigarette withdrawal. Psychopharmacology (Berlin) 120:418–425Google Scholar
  59. Tiffany ST, Drobes DJ (1991) The development and initial validation of a questionnaire on smoking urges. Br J Addict 86:1467–1476PubMedGoogle Scholar
  60. Trulson ME (1985) Activity of dopamine-containing substantia nigra neurons in freely moving cats. Neurosci Biobehav Rev 9:283–297CrossRefGoogle Scholar
  61. Trulson ME, Crisp T (1985) Chronic administration of d-amphetamine increases [3H]spiroperidol binding in cat brain. Eur J Pharmacol 117:267–270CrossRefGoogle Scholar
  62. Verebey K, Volavka J, Mule SJ, Resnick RB (1976) Naltrexone: disposition, metabolism, and effects after acute and chronic dosing. Clin Pharmacol Ther 20:315–328Google Scholar
  63. Wall ME, Brine DR, Perez-Reyes M (1981) The metabolism of naltrexone in man. NIDA Res Monogr 28:105–131Google Scholar
  64. West R (2003) Bupropion SR for smoking cessation. Expert Opin Pharmacother 4:533–540CrossRefGoogle Scholar
  65. Westman E, Levin E, Rose J (1992) Smoking while wearing the nicotine patch: is smoking satisfying or harmful? Clinical Research 40:871AGoogle Scholar
  66. Wewers ME, Dhatt RK, Snively TA, Tejwani GA (1999) The effect of chronic administration of nicotine on antinociception, opioid receptor binding and met-enkephalin levels in rats. Brain Res 822:107–113CrossRefGoogle Scholar
  67. Zacny JP, Stitzer ML (1985) Effects of smoke deprivation interval on puff topography. Clin Pharmacol Ther 38:109–115Google Scholar
  68. Zacny JP, Stitzer ML, Brown FJ, Yingling JE, Griffiths RR (1987) Human cigarette smoking: effects of puff and inhalation parameters on smoke exposure. J Pharmacol Exp Ther 240:554–564Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Margaret Rukstalis
    • 1
  • Christopher Jepson
    • 1
  • Andrew Strasser
    • 1
  • Kevin G. Lynch
    • 1
  • Kenneth Perkins
    • 2
  • Freda Patterson
    • 1
  • Caryn Lerman
    • 1
  1. 1.Tobacco Use Research CenterUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PsychiatryUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations