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

https://doi.org/10.1016/j.pscychresns.2003.12.006Get rights and content

Abstract

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two 18F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order—one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.

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)

  • L.A. Sell et al.

    Neural responses associated with cue evoked emotional states and heroin in opiate addicts

    Drug and Alcohol Dependence

    (2000)
  • E.C. Settle et al.

    Safety profile of sustained-release bupropion in depression: results of three clinical trials

    Clinical Therapeutics

    (1999)
  • H. Steinmetz et al.

    Functional anatomy of language processing: neuroimaging and the problem of individual variability

    Neuropsychologia

    (1991)
  • G.E. Swan et al.

    Abstinence effects as predictors of relapse in smokers

    Addictive Behaviors

    (1996)
  • C.T. Sweeney et al.

    Measuring drug urges by questionnaire

    Addictive Behaviors

    (1996)
  • M. Takada et al.

    Organization of ventral tegmental area cells projecting to the occipital cortex and forebrain in the rat

    Brain Research

    (1987)
  • C. Whatmough et al.

    Dissociable brain regions process object meaning and object structure during picture naming

    Neuropsychologia

    (2002)
  • L.E. Bernstein et al.

    Visual speech perception without primary auditory cortex activation

    Neuroreport

    (2002)
  • A.L. Brody et al.

    Brain metabolic changes during cigarette craving

    Archives of General Psychiatry

    (2002)
  • D. Catley et al.

    Absentminded lapses during smoking cessation

    Psychology of Addictive Behaviors

    (2000)
  • A.R. Childress et al.

    Limbic activation during cue-induced cocaine craving

    American Journal of Psychiatry

    (1999)
  • B.J. Ciliax et al.

    Immunocytochemical localization of the dopamine transporter in human brain

    Journal of Comparative Neurology

    (1999)
  • C.A. Conklin et al.

    The impact of imagining completed vs. interrupted smoking on cigarette craving

    Experimental and Clinical Psychopharmacology

    (2000)
  • B.R. Cooper et al.

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

    Neuropsychopharmacology

    (1994)
  • M.R. Daglish et al.

    Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects

    American Journal of Psychiatry

    (2001)
  • L. Dazzi et al.

    Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving rats

    Synapse

    (2002)
  • L. Dazzi et al.

    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

    (2002)
  • J. Dong et al.

    Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment

    Psychopharmacology

    (2001)
  • P.E. Downing et al.

    A cortical area selective for visual processing of the human body

    Science

    (2001)
  • M.C. Fiore et al.

    Treating Tobacco Use and Dependence. Clinical Practice Guideline

    (2000)
  • First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995. Structured Clinical Interview for DSM-IV Axis I...
  • K.J. Friston et al.

    Assessing the significance of focal activations using their spatial extent

    Human Brain Mapping

    (1994)
  • H. Garavan et al.

    Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli

    American Journal of Psychiatry

    (2000)
  • A.H. Glassman

    Cigarette smoking: implications for psychiatric illness

    American Journal of Psychiatry

    (1993)
  • S. Grant et al.

    Activation of memory circuits during cue-elicited cocaine craving

    Proceedings of the National Academy of Sciences of the USA

    (1996)
  • M. Hamilton

    Development of a rating scale for primary depressive illness

    British Journal of Social Psychology

    (1967)
  • M. Hamilton

    Diagnosis and rating of anxiety

    British Journal of Psychiatary

    (1969)
  • Cited by (127)

    • Pharmacogenetics and smoking cessation

      2019, Neuroscience of Nicotine: Mechanisms and Treatment
    • Pharmacological intervention and abstinence in smokers undergoing cessation treatment: A psychophysiological study

      2018, International Journal of Psychophysiology
      Citation 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 Opioids
    • Neuro-anatomic mapping of dopamine D<inf>1</inf> receptor involvement in nicotine self-administration in rats

      2015, Neuropharmacology
      Citation 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).

    View all citing articles on Scopus
    View full text