Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights

doi:10.1016/j.ejphar.2008.12.009

European Journal of Pharmacology

Volume 603, Issues 1–3, 28 January 2009, Pages 1-11

https://doi.org/10.1016/j.ejphar.2008.12.009 Get rights and content

Abstract

Ongoing studies continue to explore the behavioural and pharmacological effects of bupropion in smoking cessation studies and animal models of nicotine dependence. In the present review, the components of nicotine dependence that form the most likely targets of bupropion are identified within the context of an expanding preclinical and clinical literature regarding the anti-addictive properties of bupropion. Second, preclinical and clinical data that implicate specific pharmacological modes of action of bupropion in mediating the anti-smoking effects of the compound are discussed. Third, it is suggested that the unique mixed pharmacological profile of bupropion provides (1) attenuation of the multiple negative consequences of withdrawal via blockade of dopamine and noradrenaline reuptake; (2) replacement of the reward-facilitating and subjective effects of nicotine via blockade of dopaminergic reuptake; (3) attenuation of the rewarding effects of acute nicotine by nicotinic acetylcholine receptor blockade. The importance of species differences in bupropion metabolism in the interpretation of preclinical studies is highlighted. Finally, future studies are suggested to address identified gaps in the knowledge: most importantly, to provide stronger evidence for the role of noradrenaline reuptake inhibition in bupropion-induced attenuation of nicotine withdrawal. Future studies aimed at providing more evidence for the three-fold nature of the anti-smoking effects of bupropion are also suggested, along with the possibility of utilizing adjunct therapies to improve smoking cessation rates.

Introduction

Bupropion is one of the most effective anti-smoking medications currently available. Initially designed and marketed as an atypical antidepressant (Ascher et al., 1995), bupropion was recognized as having beneficial effects in smoking cessation (Ferry and Burchette, 1994) and was subsequently licensed for use as an anti-smoking agent in 1998 (USA) and 2000 (UK; Roddy, 2004). Numerous clinical studies have confirmed the efficacy of bupropion as an anti-smoking drug (e.g., Hurt et al., 1997), and recent studies have attempted to assess more closely which component of tobacco dependence is attenuated by bupropion treatment (Gonzales et al., 2006, Jorenby et al., 2006, West et al., 2008). Preclinical studies investigating the effects of bupropion in animal models of nicotine dependence have recently widened in scope from early self-administration (e.g., Glick et al., 2002a) and drug discrimination (Young and Glennon, 2002) studies to the behavioural and neurochemical indices of nicotine withdrawal (Paterson et al., 2007). Beyond the behavioural mechanisms of bupropion's anti-smoking effects, preclinical and clinical research efforts have also focused on the pharmacological effects of bupropion, which include inhibition of dopamine and noradrenaline reuptake and nicotinic acetylcholine receptor blockade (for review, see Dwoskin et al., 2006). This combination of preclinical and clinical studies aimed at delineating the behavioural and pharmacological mechanisms that underlie the anti-smoking properties of bupropion now allow a tentative mapping of the relationships between the pharmacological and behavioural effects of bupropion. It is suggested here that the three pharmacological modes of action of bupropion represent a three-pronged attack on multiple components of nicotine dependence. In addition, although preclinical studies have been valuable in contributing to our knowledge of the effects of bupropion, metabolism studies indicated that bupropion metabolism is closer in humans and mice than humans and rats. Potential implications of these differences for interpretation of the preclinical data are briefly discussed and future studies to address this issue are suggested. Finally, gaps in the bupropion literature are identified as promising avenues for future research.

Section snippets

Clinical studies

After the serendipitous identification of bupropion as a potential smoking cessation agent (Ferry and Burchette, 1994), multiple full scale clinical trials confirmed the effectiveness of bupropion above placebo. Hurt et al. (1997), in a double-blind placebo-controlled trial, demonstrated that bupropion increased smoking cessation rates, confirmed via expired carbon monoxide measurement, at 7 weeks of treatment, roughly doubling quit rates in the 150 and 300 mg/day bupropion groups compared to

Clinical studies

In clinically depressed subjects, bupropion treatment (300 mg/day for the last week of a 3-week treatment period) was associated with a low striatal DAT occupancy rate of just 14% (Meyer et al., 2002). Also, chronic administration of bupropion to healthy individuals showed either no significant (Kugaya et al., 2003) or just 26% striatal DAT occupancy (Learned-Coughlin et al., 2003). Subjects in the latter study received a higher daily dose of bupropion. In contrast with the bupropion data, the

Mapping the pharmacological to the behavioural effects of bupropion in nicotine dependence

Based on impaired dopamine neurotransmission within the nucleus accumbens shell during nicotine withdrawal in rats (e.g., Hildebrand et al., 1998), and the role of dopamine signalling in this brain region in motivational and reward-related processes (e.g., Salamone et al., 1997, Schultz, 2002, Balfour, 2004), it is likely that bupropion attenuates the anhedonic component of nicotine withdrawal by enhancing dopamine overflow within the nucleus accumbens shell (Paterson et al., 2007). In addition

Future studies

A number of future studies could add significantly to our understanding of the mechanisms underlying the anti-smoking properties of bupropion. One important and relevant future study would be to assess the effects of acute and chronic bupropion on nicotine self-administration in the mouse, due to the demonstrated nicotinic antagonist properties of bupropion in the mouse (Carrasco et al., 2006, Damaj et al., 2004, Slemmer et al., 2000) and the similar accumulation of the metabolite

Conclusion

Clinical studies indicate that bupropion is an effective anti-smoking medication that ameliorates acute nicotine withdrawal, attenuates the rewarding effects of nicotine, and may decrease cue-induced nicotine craving. Preclinical studies indicated that bupropion attenuates the aversive aspects of nicotine withdrawal in rats and the reward-facilitating effects of nicotine, although it had inconsistent effects on the rewarding properties of nicotine. Interestingly, bupropion enhances the

Acknowledgements

This work was supported by the Postdoctoral Research Fellowship 14FT-0056 from the Tobacco-Related Disease Research Program (State of California) and a Research Grant from the Peter F. McManus Charitable Trust. The author gratefully acknowledges Professor D.J. Balfour, University of Dundee, Scotland, for valuable discussions regarding the pharmacological and behavioural effects of bupropion.

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Behavioural PharmacologyBehavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights

Abstract

Introduction

Section snippets

Clinical studies

Clinical studies

Mapping the pharmacological to the behavioural effects of bupropion in nicotine dependence

Future studies

Conclusion

Acknowledgements

Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial

J. Am. Med. Assoc.

Nicotinic receptor subtypes in rat hippocampal slices are differentially sensitive to desensitization and early in vivo functional up-regulation by nicotine and to block by bupropion

J. Pharmacol. Exp. Ther.

A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement

Pharmacol. Biochem. Behav.

Bupropion: a review of its mechanism of antidepressant activity

J. Clin. Psychiatry

Efficacy of bupropion and predictors of successful outcome in a sample of French smokers: a randomized placebo-controlled trial

Addiction

Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking

Neuropychopharmacology

The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens [corrected]

Nicotine Tob. Res.

Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level

J. Neurosci.

Regulation of the noradrenaline transporter by chronic administration of antidepressants

Biol. Psychiatry

Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys

J. Pharmacol. Exp. Ther.

Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats

Psychopharmacology

Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behaviour in rats

Neuropharmacology

Characterization of nicotine's ability to serve as a negative feature in a Pavlovian appetitive conditioning task in rats

Psychopharmacology

Behavioural and biochemical investigations of bupropion metabolites

Eur. J. Pharmacol.

Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen

Behav. Brain Res.

Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study

Psychiatry Res.

Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats

Synapse

Environmental stimuli promote the acquisition of nicotine self-administration in rats

Psychopharmacology

High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behaviour and hippocampal cell proliferation

Biol. Psychiatry

Effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in mice

Prog. Neuropsychopharmacol. Biol. Psychiatry

The influence of depressive symptoms on smoking cessation among African Americans in a randomized trial of bupropion

Nicotine Tob. Res.

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

Psychopharmacology

Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement

Psychopharmacology

Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling

Nicotine Tob. Res.

Influence of fluoxetine on positive and negative affect in a clinic-based smoking cessation trial

Psychopharmacology

Behavioural and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo

J. Pharmacol. Exp. Ther.

Evidence that the acute behavioural and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism

Neuropsychopharmacology

Acute doses of d-amphetamine and bupropion increase cigarette smoking

Psychopharmacology

Efficacy of bupropion for relapse prevention in smokers with and without a past history of major depression

J. Gen. Intern. Med.

Use of dopamine-beta-hydroxylase-deficient mice to determine the role of noradrenaline in the mechanism of action of antidepressant drugs

J. Pharmacol. Exp. Ther.

Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat

Psychopharmacology

Noradrenaline-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

Proc. Natl. Acad. Sci.

Mood, major depression, and fluoxetine response in cigarette smokers

Am. J. Psychiatry

Enantioselective effects of hydroxy metabolites of bupropion on behaviour and on function of monoamine transporters and nicotinic receptors

Mol. Pharmacol.

Atomoxetine reverses nicotine withdrawal-associated deficits in contextual fear conditioning

Neuropsychopharmacology

Behavioural Pharmacology
Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights