How does bupropion work as a smoking cessation aid?

Bupropion exhibits reasonable efficacy as a smoking cessation aid, yet its precise mechanisms of action remain unclear. This review evaluates the mechanism of action of bupropion by considering the clinical evidence in combination with results from pre‐clinical experiments in vivo and in vitro. Bupropion is a weak inhibitor of dopamine and noradrenaline reuptake, and has also been shown to antagonise nicotinic acetylcholine receptor function. It is extensively metabolized in humans, its major metabolites reaching levels higher than those of bupropion itself. These metabolites share many of the pharmacological properties of bupropion, so they may play an important role in its clinical activity, yet they have been neglected in investigations into bupropion action. This review led to several conclusions: (1) the principal mode of bupropion action is upon the withdrawal symptoms following smoking cessation; (2) during withdrawal, bupropion may attenuate symptoms by mimicking nicotinic effects on dopamine and noradrenaline; (3) its ability to antagonize nicotinic receptors may prevent relapse by attenuating the reinforcing properties of nicotine, but probably cannot acutely reduce smoking; and (4) further exploration of bupropion metabolites and its role in withdrawal and relapse, within more appropriate animal models, could be crucial in the determination of the precise mechanisms by which bupropion exerts its activity in smoking cessation. Greater elucidation of the exact mechanisms of action of bupropion could lead to the development of new drugs even more beneficial in promoting smoking abstinence.

[1]  T. Carmody,et al.  Bupropion for smoking cessation , 2004, Comprehensive therapy.

[2]  E. Hudes,et al.  Bupropion for smoking cessation: a randomized trial. , 2004, Archives of internal medicine.

[3]  T. Robinson,et al.  Randomized clinical trial of the efficacy of bupropion combined with nicotine patch in the treatment of adolescent smokers. , 2004, Journal of consulting and clinical psychology.

[4]  R. Wise.  Dopamine, learning and motivation , 2004, Nature Reviews Neuroscience.

[5]  M. Jarvik,et al.  Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study , 2004, Psychiatry Research: Neuroimaging.

[6]  H. Javitz,et al.  Effectiveness of bupropion sustained release for smoking cessation in a health care setting: a randomized trial. , 2004, Archives of internal medicine.

[7]  M. Bergström,et al.  In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography , 2003, Biological Psychiatry.

[8]  A. Markou,et al.  Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats , 2003, Synapse.

[9]  R. Glennon,et al.  Behavioral and biochemical investigations of bupropion metabolites. , 2003, European journal of pharmacology.

[10]  L. Dwoskin,et al.  Effect of bupropion on nicotine self-administration in rats , 2003, Psychopharmacology.

[11]  N. Chaudhri,et al.  Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement , 2003, Psychopharmacology.

[12]  S. Tonstad,et al.  Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study. , 2003, European heart journal.

[13]  J. Cryan,et al.  Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat , 2003, Psychopharmacology.

[14]  J. Martínez-Raga,et al.  Treatment of nicotine dependence with bupropion SR: review of its efficacy, safety and pharmacological profile , 2003, Addiction biology.

[15]  M. Shoaib,et al.  Investigating the actions of bupropion on dependence-related effects of nicotine in rats , 2003, Psychopharmacology.

[16]  P. B. Gold,et al.  Naturalistic, self-assignment comparative trial of bupropion SR, a nicotine patch, or both for smoking cessation treatment in primary care. , 2002, The American journal on addictions.

[17]  L. Dwoskin,et al.  Bupropion Inhibits Nicotine-Evoked [3H]Overflow from Rat Striatal Slices Preloaded with [3H]Dopamine and from Rat Hippocampal Slices Preloaded with [3H]Norepinephrine , 2002, Journal of Pharmacology and Experimental Therapeutics.

[18]  M. Mayo,et al.  Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. , 2002, JAMA.

[19]  N. Chaudhri,et al.  Environmental stimuli promote the acquisition of nicotine self-administration in rats , 2002, Psychopharmacology.

[20]  R. Glennon,et al.  Nicotine and bupropion share a similar discriminative stimulus effect. , 2002, European journal of pharmacology.

[21]  N. Rigotti,et al.  The effect of bupropion sustained-release on cigarette craving after smoking cessation. , 2002, Clinical therapeutics.

[22]  N. Chaudhri,et al.  Cue dependency of nicotine self-administration and smoking , 2001, Pharmacology Biochemistry and Behavior.

[23]  A. Buist,et al.  Sustained-Release Bupropion for Pharmacologic Relapse Prevention after Smoking Cessation , 2001, Annals of Internal Medicine.

[24]  B. Jamerson,et al.  Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: A randomized placebo‐controlled study , 2001, Clinical pharmacology and therapeutics.

[25]  P. Anderson,et al.  Smoking cessation in patients with chronic obstructive pulmonary disease: a double-blind, placebo-controlled, randomised trial , 2001, The Lancet.

[26]  E. D. Glover,et al.  Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. , 2001, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[27]  B. Jamerson,et al.  Late-term smoking cessation despite initial failure: an evaluation of bupropion sustained release, nicotine patch, combination therapy, and placebo. , 2001, Clinical therapeutics.

[28]  M. Damaj,et al.  Bupropion is a nicotinic antagonist. , 2000, The Journal of pharmacology and experimental therapeutics.

[29]  J. Rose,et al.  Dissociating nicotine and nonnicotine components of cigarette smoking , 2000, Pharmacology Biochemistry and Behavior.

[30]  Aker,et al.  A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. , 1999, The New England journal of medicine.

[31]  C. Patten,et al.  Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism∗ , 1999, British Journal of Psychiatry.

[32]  G. Koob,et al.  Dramatic decreases in brain reward function during nicotine withdrawal , 1998, Nature.

[33]  J. A. Johnston,et al.  Pharmacokinetics of Bupropion and its Metabolites in Cigarette Smokers versus Nonsmokers , 1997, Journal of clinical pharmacology.

[34]  P. S. Grigson.  Conditioned taste aversions and drugs of abuse: a reinterpretation. , 1997, Behavioral neuroscience.

[35]  J. Feighner,et al.  Bupropion: a review of its mechanism of antidepressant activity. , 1995, The Journal of clinical psychiatry.

[36]  B. Cooper,et al.  Evidence that the Acute Behavioral and Electrophysiological Effects of Bupropion (Wellbutrin®) Are Mediated by a Noradrenergic Mechanism , 1994, Neuropsychopharmacology.

[37]  J. Lake,et al.  Rodent model of nicotine abstinence syndrome , 1992, Pharmacology Biochemistry and Behavior.

[38]  H. Fibiger,et al.  Effects of chronic bupropion on interstitial concentrations of dopamine in rat nucleus accumbens and striatum. , 1992, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[39]  T. Sharp,et al.  Effect of naloxone-precipitated morphine withdrawal on noradrenaline release in rat hippocampus in vivo. , 1992, European journal of pharmacology.

[40]  A. Puech,et al.  Antidepressant profile of bupropion and three metabolites in mice. , 1990, Pharmacopsychiatry.

[41]  W. Potter,et al.  Bupropion in depression. II. The role of metabolites in clinical outcome. , 1988, Archives of general psychiatry.

[42]  S. Markey,et al.  Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output. , 1988, Archives of general psychiatry.

[43]  T. Cooper,et al.  Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs. , 1986, Drug metabolism and disposition: the biological fate of chemicals.

[44]  R. Ferris,et al.  Bupropion: A new antidepressant drug, the mechanism of action of which is not associated with down-regulation of postsynaptic β-adrenergic, serotonergic (5-HT2), α 2-adrenergic, imipramine and dopaminergic receptors in brain , 1983, Neuropharmacology.

[45]  B. Cooper,et al.  Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo. , 1980, The Journal of pharmacology and experimental therapeutics.

[46]  W. Corrigall,et al.  Nicotine maintains robust self-administration in rats on a limited-access schedule , 2004, Psychopharmacology.

[47]  D. Kooy,et al.  The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour , 2004, Nature Reviews Neuroscience.

[48]  S. Shiffman,et al.  The effect of bupropion on nicotine craving and withdrawal , 2000, Psychopharmacology.

[49]  G Di Chiara,et al.  Role of dopamine in the behavioural actions of nicotine related to addiction. , 2000, European journal of pharmacology.

[50]  D. Schroeder,et al.  A comparison of sustained-release bupropion and placebo for smoking cessation. , 1997, The New England journal of medicine.

[51]  G. Gustavsson,et al.  Combined use of nicotine patch and gum in smoking cessation: a placebo-controlled clinical trial. , 1995, Preventive medicine.

[52]  I. Stolerman,et al.  The neurobiology of tobacco addiction. , 1991, Trends in pharmacological sciences.

[53]  B. Cooper,et al.  Neurochemical and neuropharmacological investigations into the mechanisms of action of bupropion . HCl--a new atypical antidepressant agent. , 1982, Advances in biochemical psychopharmacology.