Nicotine-dependent smokers treated with bupropion report significantly greater reductions in craving and exhibited reduced activation in the ventral striatum, medial orbitofrontal cortex, and anterior cingulate cortex when resisting craving compared with smokers treated with placebo. When assessing these specific regions, activation changes correlated positively with changes in craving from before to after treatment. The bupropion-treated group alone exhibited reduced activation in the anterior cingulate cortex and in secondary visual processing centers while resisting craving. While no craving or activation differences were observed between treatment groups before treatment, bupropion-treated participants reported significantly less craving and exhibited less ventral striatum and anterior cingulate cortex activation than placebo-treated participants when resisting craving after treatment. These results demonstrate that treatment with bupropion is associated with an improved ability to resist cue-induced craving and a reduction in cue-induced activation of limbic and prefrontal brain regions.
Our findings complement previous research demonstrating that nicotine-dependent smokers exhibit activation in the anterior cingulate cortex and ventral striatum as well as other brain regions that integrate information regarding executive function (prefrontal cortex), prior experience (hippocampus), emotion (amygdala), and reward (ventral tegmental area) while viewing smoking-related cues.40-45
Bupropion treatment attenuates cue-induced metabolism in the anterior cingulate cortex58
and, as demonstrated here, cue-induced activation of this region and other brain regions (ventral striatum and medial orbitofrontal cortex) known to be involved in drug craving and addiction.81,82
Activation changes in these brain regions correlated with a reduction in craving, suggesting that modulation of limbic and prefrontal function associated with bupropion treatment may directly influence subjective craving.
The association between craving and brain activation observed during the crave-resist condition, irrespective of treatment, parallels previous research demonstrating a relationship between drug craving and activation of brain regions that are responsible for emotional and cognitive appraisal (anterior cingulate cortex) and conditioned reinforcement (medial orbitofrontal cortex).40,70,82
Bupropion-treated participants exhibited reduced activation in these specific regions while resisting craving compared with placebo-treated participants. These findings further support the role of prefrontal regions in mediating cue-induced craving and support the primary finding of this study that bupropion treatment modulates activation in the anterior cingulate and medial orbitofrontal cortices.
Bupropion is reported to enhance smoking cessation by altering basal levels of dopamine though inhibition of dopamine reuptake while simultaneously modulating phasic dopamine release in the ventral striatum in response to smoking or smoking-related cues.9,16,17,21,33,83-85
Although fMRI data remain difficult to interpret in the context of specific neurotransmitters, our results demonstrate that bupropion treatment induced changes in the dopamine-rich ventral striatum and functionally related anterior cingulate cortex86
and medial orbitofrontal cortex. The anterior cingulate cortex collects information from limbic and prefrontal regions to assess the salience of emotional and motivational information, while the ventral striatum works in concert to mediate reward, particularly for drugs,87,88
as well as predict and act on the presence of reward.25,89
Research combining positron emission tomography and fMRI imaging has verified this functional association and revealed a positive correlation between dopamine synthesis capacity in the ventral striatum and blood oxygen level–dependent signal increases in the anterior cingulate cortex elicited by rewarding stimuli.90
Hence, modulation of dopamine signaling in the ventral striatum via bupropion may alter reward signaling to the anterior cingulate cortex and associated prefrontal regions, attenuating affective appraisal of smoking cues and relative reward salience, thereby leading to a reduction in craving.
Although no treatment-induced changes were seen in regions previously shown to differ when untreated smokers allow or resist craving,70
the associations between craving and brain activation observed under these 2 conditions varied considerably. During the crave-allow condition, placebo-treated participants exhibited an association between changes in craving and activation in default mode networks (posterior cingulate cortex, precuneus)91
and brain regions associated with imitation (frontal lobe, premotor cortex, superior parietal lobe, inferior frontal cortex92
). This finding suggests that placebo- treated participants who reported less craving during the crave-allow condition were less engaged by the smoking-related cues. This effect was not observed in the bupropion-treated smokers or the combined sample (both treatment groups). Considering these findings, instructing smokers to allow cue-induced craving elicits brain activation associated with mentally mimicking or imagining smoking behavior while encouraging them to resisting craving influences brain regions that relate to conditioned reward and affective appraisal, providing amore relevant state for assessing smoking cessation therapies.
While published articles demonstrate roughly 35% to 40% short-term abstinence rates with bupropion treatment,3,4
we expected a quit rate of approximately 20% in our bupropion-treated smokers because we did not provide concomitant behavioral intervention along with the medication administration as in prior studies. We did not include behavioral intervention in order to isolate the effects of bupropion treatment on regional brain activation. Although the bupropion-treated participants exhibited significantly greater reductions in FTND scores and exhaled carbon monoxide from before to after treatment and lower FTND scores after treatment (), no significant between-group difference was observed in cigarettes per day (though bupropion- treated smokers did, on average, have a greater reduction in this measure). The discrepancies between objective (exhaled carbon monoxide) and self-reported (cigarettes per day) smoking measures reported in placebo- treated smokers may reflect the desire of research participants to please study researchers. In addition to controlling for nicotine consumption in our primary analysis, we also replicated the primary finding of this study, excluding participants who quit smoking during treatment (bupropion, n = 3; placebo, n = 1) to ensure that the unbalanced number of quitters in each group did not unintentionally influence our findings (eFigure; http://www.archgenpsychiatry.com
In summary, a standard course of treatment with bupropion enhances the ability of smokers to resist cueinduced craving, measured as reductions in self-reported craving and reduced activation in the ventral striatum, anterior cingulate, and medial orbitofrontal cortex.