Abstract
Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and $50 billion in medical costs annually are directly attributed to smoking1. Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction2, but the means by which nicotine produces addiction remain unclear. Nicotine is less effective as a positive reinforcer than other drugs of abuse in non-dependent animals3. Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving4,5 in dependent subjects may contribute to the addictive liability of nicotine6,7. We show here that spontaneous nicotine withdrawal in rats resulted in a significant decrease in brain reward function, as measured by elevations in brain reward thresholds, which persisted for four days. Further, systemic injections of a competitive nicotinic-receptor antagonist8 led to a dose-dependent increase in brain reward thresholds in chronic nicotine-treated rats. The decreased function in brain reward systems during nicotine withdrawal is comparable in magnitude and duration to that of other major drugs of abuse9,10,11,12,13, and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans7.
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References
Malarcher, A. M., Chrismon, J. H., Giovino, G. A. & Erikson, M. P. Smoking-attributable mortality and years of potential life lost—United States, 1984. Morb. Mort. Weekly Rep. 46, 444–451 (1997).
Stolerman, I. P. & Jarvis, M. J. The scientific case that nicotine is addictive. Psychopharmacology 117, 2–10 (1995).
Risner, M. E. & Goldberg, S. R. Acomparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. J. Pharmacol. Exp. Ther. 224, 319–326 (1983).
US Department of Health and Human Services. The Health Consequences of Smoking: Nicotine Addiction: A Report of the U.S. Surgeon General. (US Government Printing Office, WashingtonD, (1988).
Hughes, J. R., Gust, S. W., Skoog, K., Keenan, R. M. & Fenwick, J. W. Symptoms of tobacco withdrawal: a replication and extension. Arch. Gen. Psychiatry 48, 52–59 (1991).
Shiffman et al. Progression from a smoking lapse to relapse: prediction from abstinence violation effects, nicotinedependenc, and lapse characteristics. J. Consult. Clin. Psychol. 64, nicotinedependenc 993–1002 (1996).
Markou, A., Kosten, T. R. & Koob, G. F. Neurobiological similarities in depression and drug dependence: a self medication hypothesis. Neuropsychopharmacology 18, 135–174 (1998).
Damaj, M. I., Welch, S. P. & Martin, B. R. In vivo pharmacological effects of dihydro-β-erythroidine, a nicotinic antagonist, in mice. Psychopharmacology 117, 67–73 (1995).
Leith, N. J. & Barrett, R. J. Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia 46, 19–25 (1976).
Markou, A. & Koob, G. F. Postcocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology 4, 17–26 (1991).
Markou, A. & Koob, G. F. Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations. Physiol. Behav. 51, 111–119 (1992).
Schulteis, G., Markou, A., Gold, L. H., Stinus, L. & Koob, G. F. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose–response analysis. J. Pharmacol. Exp. Ther. 271, 1391–1398 (1994).
Schulteis, G., Markou, A., Cole, M. & Koob, G. F. Decreased brain reward produced by ethanol withdrawal. Proc. Natl Acad. Sci. USA 92, 5880–5884 (1995).
Okamoto, M., Rosenberg, H. C. & Boisse, N. R. Withdrawal chracteristics following chronic pentobarbital dosing. Eur. J. Pharmacol. 40, 107–119 (1976).
Gellert, V. F. & Holzman, S. G. Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions. J. Pharmacol. Exp. Ther. 205, 536–546 (1978).
Mendelson, J. H. & Mello, N. K. Medical progress: biological concomitants of alcoholism. N. Engl. J. Med. 301, 912–921 (1979).
Malin, D. H. et al. Rodent model of nicotine abstinence syndrome. Pharmacol. Biochem. Behav. 43, 779–784 (1992).
Hildebrand, B. E., Nomikos, G. G., Bondjers, C., Nisell, M. & Svensson, T. H. Behavioral manifectations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms. Psychopharmacology 129, 348–356 (1997).
Malin, D. H. et al. The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 115, 180–184 (1994).
Malin, D. H., Lake, J. R., Carter, V. A., Cunningham, J. S. & Wilson, O. B. Naloxone precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 112, 339–342 (1993).
Murrin, C. L., Ferrer, J. R., Wanyun, Z. & Haley, N. J. Nicotine administration to rats: methodological considerations. Life Sci. 40, 1699–1708 (1987).
Benowitz, N. L. Pharmacological aspects of cigarette smoking and nicotine addiction. N. Engl. J. Med. 319, 1318–1330 (1988).
Huston-Lyons, D. & Kornetsky, C. Effects of nicotine on the threshold for rewarding brain stimulation in rats. Pharmacol. Biochem. Behav. 41, 755–759 (1992).
Bauco, P. & Wise, R. A. Potentiation of lateral hypothalamic and midline mesencephalic brain stimulation reinforcement by nicotine: examination of repeated treatment. J. Pharmacol. Exp. Ther. 271, 294–301 (1994).
Nisell, M., Nomikos, G. G. & Svensson, T. H. Infusion of nicotine in the central tegmental area or the nucleus accumbens of the rat differentially affects accumbal dopamine release. Pharmacol. Toxicol. 75, 348–352 (1994).
Pontieri, F. E., Tanda, G., Orzi, F. & DiChiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257 (1996).
Killen, J. D., Fortmann, S. P., Newman, B. & Varady, A. Prospective study of factors influencing the development of craving associated with smoking cessation. Psychopharmacology 105, 191–196 (1991).
Hughes, J. R. et al. Smoking cessation among self-quitters. Health Psychol. 11, 331–334 (1992).
Doherty, K., Kinnunen, T., Militello, F. S. & Garvey, A. J. Urges to smoke during the first month of abstinence: relationship to relapse and predictors. Psychopharmacology 119, 171–178 (1995).
Kornetsky, C. & Esposito, R. U. Euphorigenic drugs: effects on the reward pathways of the brain. Fed. Proc. 38, 2473–2476 (1979).
Acknowledgements
This research was funded by a Novartis grant to A.M., National Institute on Drug Abuse (NIDA, USA) grants to A.M. and G.F.K., and a HIDA Individual National Research Service Award to M.P.E.-J. This is publication number 11286-NP from The Scripps Research Institute. We thank M.Arends for assistance with manuscript preparation.
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Epping-Jordan, M., Watkins, S., Koob, G. et al. Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393, 76–79 (1998). https://doi.org/10.1038/30001
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DOI: https://doi.org/10.1038/30001
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