Smoking-induced change in intrasynaptic dopamine concentration: Effect of treatment for Tobacco Dependence

https://doi.org/10.1016/j.pscychresns.2009.06.004Get rights and content

Abstract

The aim of this study was to determine whether standard treatments for Tobacco Dependence affect smoking-induced changes in intrasynaptic dopamine (DA) concentration. Forty-three otherwise healthy adult cigarette smokers (10 to 40 cigarettes per day) were treated with either practical group counseling (PGC) psychotherapy (n = 14), bupropion HCl (n = 14), or matching pill placebo (n = 15) (random assignment) for 8 weeks. Before and after treatment, each subject underwent a bolus-plus-continuous-infusion 11C-raclopride positron emission tomography (PET) scanning session, during which he or she smoked a regular cigarette. The PET scanning outcome measure of interest was percent change in smoking-induced 11C-raclopride binding potential (BPND) in the ventral caudate/nucleus accumbens (VCD/NAc), as an indirect measure of DA release. Although the entire study sample had a smaller mean smoking-induced reduction in VCD/NAc BPND after treatment (compared to before treatment), this change was highly correlated with smaller total cigarette puff volumes (and not other treatment variables). These data indicate that smoking-induced DA release is dose-dependent, and is not significantly affected by reductions in daily smoking levels or treatment type.

Introduction

Recent studies using the radiotracer 11C-raclopride and positron emission tomography (PET) have demonstrated (indirectly) that cigarette smoking (Brody et al., 2004, Brody et al., 2006, Scott et al., 2007) and nicotine intake (Takahashi et al., 2008) increase intrasynaptic dopamine (DA) concentration in the ventral striatum/nucleus accumbens (VST/NAc) in human smokers (though not all studies using these and similar methods have shown this effect (Tsukada et al., 2002, Barrett et al., 2004, Montgomery et al., 2007)). In these studies, DA release has been associated with the craving–reducing (Brody et al., 2004, Brody et al., 2006) and pleasurable (Barrett et al., 2004, Brody et al., 2009) effects of smoking, as well as the severity of nicotine dependence (Scott et al., 2007). Nicotine-induced DA release has also been demonstrated in studies of non-human primates using similar methodology (Dewey et al., 1999, Tsukada et al., 2002, Marenco et al., 2004) and in rodents using microdialysis (Di Chiara and Imperato, 1988, Damsma et al., 1989, Pontieri et al., 1996, Sziraki et al., 2001). Despite these findings that point to the importance of striatal DA release in response to cigarette smoking, the effects of treatment for Tobacco Dependence (TD) on smoking-induced DA release have not been reported.

Currently, there are several effective first-line treatments for TD, including (but not limited to) the medication bupropion HCl (Zyban) and the psychotherapy ‘practical group counseling’ (PGC) (Marlatt and Gordon, 1985, Carmody, 1990, Fiore et al., 2000, Hall et al., 2002, Gold et al., 2002, Abrams et al., 2003, Holmes et al., 2004). A standard (2-month) course of treatment with bupropion HCl (administered along with brief counseling) results in abstinence rates of roughly 40% (Hurt et al., 1997), with longer term (12-month) abstinence rates of about 20 to 30% (Jorenby et al., 1999, Simon et al., 2004, Paluck et al., 2006). Abstinence rates with medication alone are typically lower than those achieved with the combination of medication plus psychotherapy (Hall et al., 2002). Similar to medication administered alone, PGC typically results in abstinence rates of about 40% after 2 months and 20% after 6 months of treatment (Fiore et al., 1994), with a recent literature review concluding that group psychotherapies have roughly twice the abstinence rates of control conditions (Stead and Lancaster, 2005).

The complete biological pathway by which bupropion HCl assists smokers in quitting remains uncertain (Horst and Preskorn, 1998, Foley et al., 2006); however, there is evidence for either diminished or unchanged smoking-induced DA release with bupropion HCl treatment. As for evidence of diminished smoking-induced DA release, the most commonly demonstrated mechanism of action for bupropion HCl is inhibition of pre-synaptic DA reuptake (Horst and Preskorn, 1998, Balfour, 2001, Stahl et al., 2004), with reports of both acute (Nomikos et al., 1989) and chronic (Ascher et al., 1995) increases in extracellular DA in the VST/NAc. In addition, a brain imaging study of subjects with depression (Argyelan et al., 2005) demonstrated that chronic bupropion HCl treatment is associated with diminished dopamine transporter availability, which would presumably increase intrasynaptic DA since the dopamine transporter is primarily responsible for clearance of intrasynaptic DA (Hoffman et al., 1998). These studies suggest that chronic bupropion HCl treatment leads to increased intrasynaptic DA, which would be expected to result in a downregulation of D2 receptors and diminished DA release in response to pharmacological stimuli (Bilder et al., 2004, Nikolaus et al., 2007a, Nikolaus et al., 2007b, Bamford et al., 2008). As for evidence of unchanged smoking-induced DA release, a recent study of rodents demonstrated that chronic bupropion HCl treatment increases extracellular DA in the nucleus accumbens shell, but does not alter the reward-facilitating effects of experimenter-administered nicotine (Paterson et al., 2007). In addition, a study of human smokers examining the effects of bupropion HCl treatment on the pleasurable effect of smoking (a symptom presumably associated with DA release (Barrett et al., 2004, Brody et al., 2009)) demonstrated no change in the pleasurable effect of a lapse cigarette (McCarthy et al., 2008). Thus, taken together, these studies suggest that a course of bupropion HCl treatment would lead to increased intrasynaptic DA and diminished smoking-induced DA release, although there is also evidence to suggest that smoking-induced DA release would be unaffected by bupropion HCl treatment.

As for practical group counseling (PGC) for TD, we are not aware of any studies examining its mechanism of action. However, it is hypothesized that talk therapy in general (as a learning experience) leads to changes in synaptic plasticity (Marlatt and Gordon, 1985, Carmody, 1990), through a retraining of implicit memory systems (Amini et al., 1996, Liggan and Kay, 1999). In addition, prior studies of other neuropsychiatric conditions indicate that changes in the brain with talk therapy typically have at least some overlap with those seen with effective medication (Roffman et al., 2005).

The goal of the study presented here was to determine if standard, first-line treatments for TD (bupropion HCl and PGC, compared to a pill placebo that matched bupropion HCl) affect smoking-induced increases in intrasynaptic DA concentration in tobacco-dependent cigarette smokers. Based on both human and animal studies, we hypothesized that these treatments would diminish smoking-induced changes in intrasynaptic DA concentration, though it was noted that there is also evidence for an absence of an effect of these treatments on smoking-induced DA release. We also sought to determine if treatment-related changes in smoking-induced DA release were associated with changes in the amount of a cigarette smoked during scanning, the number of cigarettes smoked per day, or withdrawal symptoms, hypothesizing that reduced smoking during scanning, cigarettes per day, or withdrawal symptoms would be associated with diminished smoking-induced DA release.

Section snippets

Research participants

Two hundred and ten subjects were screened initially during a telephone interview, in which medical, psychiatric, and substance abuse histories were obtained without personal identifiers. All subjects who were qualified and wished to participate received a complete description of the study in-person, and gave written informed consent, using forms approved by the local institutional review board. Participants were then evaluated further using screening questions from the Structured Clinical

General study population characteristics

At baseline, the entire study sample consisted of adults (mean ± standard deviation  40.3 ± 11.0 years of age), who smoked 24.2 (±6.2) cigarettes per day, had been smoking for an average of 21.6 (±11.2) years, and were mostly men (27 men, 16 women) (Table 1). Subjects were moderate-to-severely nicotine dependent (FTND mean score  6.5 ± 1.9), had minimal depression (mean total HAM-D 17 score of 1.6 ± 1.7) or anxiety (mean total HAM-A score of 2.0 ± 2.4), had a mean exhaled CO of 19.9 (±9.8) parts per million

Discussion

The central finding of this study was a reduction in smoking-induced change in 11C-raclopride binding potential (BPND) from pre- to post-treatment that was correlated with the total puff volume of a cigarette smoked during scanning. There were no significant associations between the PET measure and treatment type, quit status, or withdrawal symptoms. Because percent change in 11C-raclopride BPND is an indirect measure of change in intrasynaptic DA concentration (and therefore DA release), the

Acknowledgements

Supported by the Tobacco-Related Disease Research Program (A.L.B. [11RT-0024 and 16RT-0098]), the National Institute on Drug Abuse (A.L.B. [R01 DA15059 and DA20872]), a Veterans Affairs Type I Merit Review Award (A.L.B.), and the Office of National Drug Control Policy (E.D.L [DABT63-00-C-1003]). The authors thank Josephine Ribe and Michael Clark for their technical support in performing positron emission tomography and magnetic resonance imaging scans, respectively.

References (73)

  • S. Janhunen et al.

    Comparison of the effects of nicotine and epibatidine on the striatal extracellular dopamine

    European Journal of Pharmacology

    (2004)
  • M.E. Jarvik et al.

    Nicotine blood levels and subjective craving for cigarettes

    Pharmacology Biochemistry and Behavior

    (2000)
  • A.A. Lammertsma et al.

    Simplified reference tissue model for PET receptor studies

    Neuroimage

    (1996)
  • D.B. Abrams et al.

    The tobacco dependence treatment handbook: a guide to best practices

    (2003)
  • F. Amini et al.

    Affect, attachment, memory: contributions toward psychobiologic integration

    Psychiatry

    (1996)
  • J.A. Ascher et al.

    Bupropion: a review of its mechanism of antidepressant activity

    Journal of Clinical Psychiatry

    (1995)
  • D.J. Balfour

    The pharmacology underlying pharmacotherapy for tobacco dependence: a focus on bupropion

    International Journal of Clinical Practice

    (2001)
  • S.P. Barrett et al.

    The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [(11)C]raclopride

    Synapse

    (2004)
  • M.E. Benwell et al.

    Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain

    Journal of Neurochemistry

    (1988)
  • R.M. Bilder et al.

    The catechol-o-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes

    Neuropsychopharmacology

    (2004)
  • C.R. Breese et al.

    Effect of smoking history on [3H]nicotine binding in human postmortem brain

    Journal of Pharmacology and Experimental Therapeutics

    (1997)
  • A.L. Brody et al.

    Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette

    Neuropsychopharmacology

    (2009)
  • A.L. Brody et al.

    Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens

    Archives of General Psychiatry

    (2006)
  • A.L. Brody et al.

    Smoking-induced ventral striatum dopamine release

    American Journal of Psychiatry

    (2004)
  • T.P. Carmody

    Preventing relapse in the treatment of nicotine addiction: current issues and future directions

    Journal of Psychoactive Drugs

    (1990)
  • R.E. Carson et al.

    Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion

    Journal of Cerebral Blood Flow and Metabolism

    (1997)
  • S.L. Dewey et al.

    A pharmacologic strategy for the treatment of nicotine addiction

    Synapse

    (1999)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proceedings of the National Academy of Sciences of the United States of America

    (1988)
  • E. Ehrin et al.

    Synthesis of [methoxy-H-3]- and [methoxy-C-11]— labeled raclopride — specific dopamine-D2 receptor ligands

    Journal of Labelled Compounds & Radiopharmaceuticals

    (1987)
  • L. Farde et al.

    Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET

    Science

    (1986)
  • M.C. Fiore et al.

    Treating tobacco use and dependence

    (2000)
  • M.B. First et al.

    Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition (SCID-I/P, version 2.0)

    (1995)
  • K.F. Foley et al.

    Bupropion: pharmacology and therapeutic applications

    Expert Reviews of Neurotherapy

    (2006)
  • 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

    American Journal of Addiction

    (2002)
  • S.M. Hall et al.

    Psychological intervention and antidepressant treatment in smoking cessation

    Archives of General Psychiatry

    (2002)
  • M. Hamilton

    Development of a rating scale for primary depressive illness

    British Journal of Social Psychology

    (1967)
  • Cited by (27)

    • Is there sufficient evidence that cannabis use is a risk factor for psychosis?

      2020, Risk Factors for Psychosis: Paradigms, Mechanisms, and Prevention
    • Substance use, medication adherence and outcome one year following a first episode of psychosis

      2016, Schizophrenia Research
      Citation Excerpt :

      Although nicotine dependence appears to be a risk factor for psychosis (Gurillo et al., 2015) and a predictor of worse clinical and social outcome in psychosis patients (Krishnadas et al., 2012), why this should be is still unclear (Gurillo et al., 2015; Krishnadas et al., 2012). One possibility is that chronic nicotine use dysregulated dopamine signaling (Brody et al., 2010). Our results indicate a role for medication adherence in the association between nicotine dependence and non-remission.

    • PET imaging for addiction medicine: From neural mechanisms to clinical considerations

      2016, Progress in Brain Research
      Citation Excerpt :

      Moreover, first attempts have been made to use PET to study the effectiveness of treatments. Brody et al. (2010) studied the effects of therapy on striatal DA release in smokers while having a cigarette in the scanner. All smokers had lower smoking-induced DA reductions after treatment, although this effect was due to the cigarette volume consumption and not due to treatment type.

    • Dual role of nicotine in addiction and cognition: A review of neuroimaging studies in humans

      2014, Neuropharmacology
      Citation Excerpt :

      Molecular brain imaging studies of the human (and non-human primate) VST DA system also strongly support the importance of this pathway in the pathophysiology of human tobacco dependence. Many studies have demonstrated that inhaled tobacco smoke can displace 11C-raclopride from VST DA D2/3 receptors in human smokers (Barrett et al., 2004; Brody et al., 2004b, 2006b, 2010, in press; Domino et al., 2012a,b; Scott et al., 2007), showing that smoking behavior produces in vivo VST DA release. Although insufflated nicotine did not produce a group difference in VST DA release, the degree of change among smokers was correlated with positive feeling states; this lack of effect of nicotine nasal spray was attributed to the fact that “cigarette smoking is more likely to have activated reward circuitry than intranasal nicotine” (Montgomery et al., 2007).

    • Common and distinct neural targets of treatment: Changing brain function in substance addiction

      2013, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      This latter comparison could also help elucidate whether the observed concurrence of regional brain activity, particularly in the regions of overlap, represents treatment effects or treatment response since changes in activation could be due to symptom improvement rather than serve as the mechanism of action of the intervention. In addition, incorporating measures of brain connectivity [e.g., (Cole et al., 2010; Hong et al., 2009; Konova et al., 2013)], structure [e.g., (Froeliger et al., 2010)], electrocortical activity [e.g., (Horrell et al., 2010)], and neurochemistry [e.g., (Brody et al., 2010; Martinez et al., 2011; Schmaal et al., 2012b)], to these studies could provide further insights into the neural mechanisms of addiction treatment. Specifically, although in the present meta-analysis we focused on studies using fMRI and FDG-PET, the neuroimaging techniques most commonly used to study the neural correlates of addiction and its treatment, it is worth noting that techniques such as electroencephalogram (EEG) and magnetic resonance spectroscopy (MRS) can provide complementary information about the temporal aspects of and neurotransmitter systems affected by specific interventions.

    View all citing articles on Scopus
    View full text