Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study
Introduction
In cigarette smokers attempting abstinence, craving is associated with relapse into usage (Niaura et al., 1989b, Swan et al., 1996, Killen and Fortmann, 1997, Catley et al., 2000). Craving for cigarettes occurs naturally within the first several hours of abstinence in nicotine dependent smokers (Schuh and Stitzer, 1995, Jarvik et al., 2000), and can also be elicited reliably in the laboratory through exposure to cigarette-related cues (Sayette and Hufford, 1994, Droungas et al., 1995, Mucha et al., 1998, Morgan et al., 1999, Mucha et al., 1999, Conklin et al., 2000, Taylor et al., 2000, Brody et al., 2002). Using positron emission tomography (PET), our group recently reported that exposure to cigarette-related cues results in regional brain metabolic activation of the perigenual/ventral anterior cingulate cortex (ACC) in untreated smokers (Brody et al., 2002). We also found positive correlations between intensity of cigarette craving and relative glucose metabolism in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior insula. These findings are consistent with brain imaging studies of exposure to cues for dependent drugs other than nicotine, in which ACC activation and similar correlations between craving and brain activity have been reported (Grant et al., 1996, Maas et al., 1998, Childress et al., 1999, Volkow et al., 1999, Garavan et al., 2000, Sell et al., 2000, Daglish et al., 2001, Kilts et al., 2001, Wexler et al., 2001, Bonson et al., 2002). While the brain structures that are associated with craving in untreated substance-dependent subjects have been described, no one has yet reported the effects of standardized treatment on regional brain activation associated with exposure to drug-related cues. A better understanding of the neural substrates of medication effects on cue-induced cigarette craving may, in the future, lead to improved treatments for nicotine dependence.
Bupropion HCl is an effective, first-line medication for nicotine dependence (Hurt et al., 1997, Jorenby et al., 1999, Fiore et al., 2000). In addition to its overall efficacy for promoting smoking abstinence, treatment with bupropion HCl results in decreased overall levels of craving (Durcan et al., 2002) and other symptoms of nicotine withdrawal, such as depression and irritability (Shiffman et al., 2000). Despite the widespread use of bupropion HCl for nicotine dependence, no study to date has reported the effects of this medication on brain function in subjects with nicotine dependence.
In this preliminary study, we compared bupropion-treated with untreated smokers in both clinical and brain metabolic responses to cigarette-related (compared with neutral) cues. We also investigated associations between cigarette craving and regional brain metabolism in bupropion-treated subjects to determine if brain regions that mediate craving in untreated smokers also mediate craving in treated smokers. We hypothesized that (1) smokers treated with bupropion HCl would have less overall and cue-induced craving than untreated smokers; (2) bupropion-treated smokers would have less cue-induced metabolic activation of the perigenual/ventral ACC [only the ACC was studied here because it is the only region consistently found to activate in prior drug craving studies and in our previous study of brain mediation of cigarette craving (Brody et al., 2002)]; and (3) positive correlations between intensity of craving and regional metabolism in the OFC, DLPFC, and anterior insula (found in untreated smokers) would remain intact in bupropion-treated smokers.
Section snippets
Subjects
Thirty-seven otherwise healthy smokers (≥20 cigarettes/d) were recruited through local newspaper advertisements. Twenty subjects had no treatment for smoking cessation prior to PET scanning and results from that group are reported elsewhere (Brody et al., 2002), while 17 subjects underwent short-term standardized treatment with bupropion HCl (as described below) prior to PET scanning. Subjects were adults (21–65 years of age) and were screened initially during a telephone interview in which
Sample characteristics and clinical results
Prior to treatment, the bupropion-treated and untreated groups were similar in age, number of cigarettes smoked per day, number of years smoking, and exhaled CO levels (Student's t test, all P>0.05) (Table 1). The groups were also similar in sex, handedness, and interval between scans. HAM-D and HAM-A scores were low overall, and were similar between groups (see Table 1, Student's t-tests, all P>0.05).
Following treatment, bupropion-treated smokers had lower Urge to Smoke (UTS) Scale scores
Discussion
In this study, smokers treated with bupropion HCl had lower overall cigarette craving and less cue-induced cigarette craving than untreated smokers. This diminished cue-induced cigarette craving was accompanied by reduced activation of perigenual/ventral ACC metabolism, possibly related to increased neutral state metabolism in this region. In bupropion-treated smokers, intensity of craving was associated with normalized metabolism in the OFC bilaterally [similar to untreated smokers (Brody et
Acknowledgements
The research reported was supported by a Veterans Affairs Type I Merit Review Award (A.L.B.), the Tobacco-Related Disease Research Program (A.L.B. [7KT-0098 and 11RT-0024] and E.D.L. [10RT-0091]), the National Institute on Drug Abuse (A.L.B. [R01 DA15059] and E.D.L. [RO1 DA14093]), and the National Institute of Mental Health (S.S. [K23 MH001694]). The authors thank Nayda Quinones and Michael Clark for technical support in performing PET and MRI scans, respectively. An earlier version of this
References (75)
- et al.
Neural systems and cue-induced cocaine craving
Neuropsychopharmacology
(2002) - et al.
Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs
European Neuropsychopharmacology
(2001) - et al.
Effect of smoking cues and cigarette availability on craving and smoking behavior
Addictive Behaviors
(1995) - et al.
The effect of bupropion sustained-release on cigarette craving after smoking cessation
Clinical Therapeutics
(2002) - et al.
Decision-making in a risk-taking task: a PET study
Neuropsychopharmacology
(2002) - et al.
Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion
Journal of Affective Disorders
(1998) - et al.
Nicotine blood levels and subjective craving for cigarettes
Pharmacology Biochemistry and Behavior
(2000) - et al.
Responses to smoking-related stimuli and early relapse to smoking
Addictive Behaviors
(1989) - et al.
Reactivity to high risk situations and smoking cessation outcome
Journal of Substance Abuse
(1989) - et al.
Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex
Neuropsychopharmacology
(2002)
Neural responses associated with cue evoked emotional states and heroin in opiate addicts
Drug and Alcohol Dependence
Safety profile of sustained-release bupropion in depression: results of three clinical trials
Clinical Therapeutics
Functional anatomy of language processing: neuroimaging and the problem of individual variability
Neuropsychologia
Abstinence effects as predictors of relapse in smokers
Addictive Behaviors
Measuring drug urges by questionnaire
Addictive Behaviors
Organization of ventral tegmental area cells projecting to the occipital cortex and forebrain in the rat
Brain Research
Dissociable brain regions process object meaning and object structure during picture naming
Neuropsychologia
Visual speech perception without primary auditory cortex activation
Neuroreport
Brain metabolic changes during cigarette craving
Archives of General Psychiatry
Absentminded lapses during smoking cessation
Psychology of Addictive Behaviors
Limbic activation during cue-induced cocaine craving
American Journal of Psychiatry
Immunocytochemical localization of the dopamine transporter in human brain
Journal of Comparative Neurology
The impact of imagining completed vs. interrupted smoking on cigarette craving
Experimental and Clinical Psychopharmacology
Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism
Neuropsychopharmacology
Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects
American Journal of Psychiatry
Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving rats
Synapse
Inhibition by venlafaxine of the increase in norepinephrine output in rat prefrontal cortex elicited by acute stress or by the anxiogenic drug FG 7142
Journal of Psychopharmacology
Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment
Psychopharmacology
A cortical area selective for visual processing of the human body
Science
Treating Tobacco Use and Dependence. Clinical Practice Guideline
Assessing the significance of focal activations using their spatial extent
Human Brain Mapping
Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli
American Journal of Psychiatry
Cigarette smoking: implications for psychiatric illness
American Journal of Psychiatry
Activation of memory circuits during cue-elicited cocaine craving
Proceedings of the National Academy of Sciences of the USA
Development of a rating scale for primary depressive illness
British Journal of Social Psychology
Diagnosis and rating of anxiety
British Journal of Psychiatary
Cited by (127)
Pharmacogenetics and smoking cessation
2019, Neuroscience of Nicotine: Mechanisms and TreatmentPotential psychological & neural mechanisms in binge eating disorder: Implications for treatment
2018, Clinical Psychology ReviewPharmacological intervention and abstinence in smokers undergoing cessation treatment: A psychophysiological study
2018, International Journal of PsychophysiologyCitation Excerpt :Although these may highlight the sensitivity of psychophysiological measures compared with self-reported assessments, future studies need to address such discrepancy. To conclude, our study represents an initial attempt to use psychophysiological approaches to identifying the shorter-term and longer-term effects of bupropion and varenicline on emotional reactivity, extending previous research in cessation medications' effects on cognitive processes (Rhodes et al., 2012; Austin et al., 2014) and cue reactivity (Brody et al., 2004; Culbertson et al., 2011). Research in various domains (e.g., affect and cognition) will help elucidate the therapeutic mechanisms of smoking cessation medications, allowing the development of more effective smoking cessation treatments.
Nicotine Dependence and the Anterior Cingulate-Precuneus Pathway: Using Neuroimaging to Test Addiction Theories
2016, Neuropathology of Drug Addictions and Substance Misuse Volume 1: Foundations of Understanding, Tobacco, Alcohol, Cannabinoids and OpioidsNeuro-anatomic mapping of dopamine D<inf>1</inf> receptor involvement in nicotine self-administration in rats
2015, NeuropharmacologyCitation Excerpt :There is ample evidence that the ACC plays a role in the process of drug addiction. Human imaging studies have repeatedly implicated the ACC in the processing of visual stimuli associated with tobacco use; activity that has shown to positively correlate with cigarette cravings in smokers (Brody et al., 2004, 2002; Canterberry et al., 2013; McClernon et al., 2005; Zubieta et al., 2005). Pharmacological inactivation of the ACC has been shown to reduce cue-induced reinstatement to cocaine in rats (McLaughlin and See, 2003), and reduce contextual coding during extinction training (Torregrossa et al., 2013).