Elsevier

Biological Psychiatry

Volume 68, Issue 8, 15 October 2010, Pages 719-725
Biological Psychiatry

Archival Report
Nicotine Withdrawal Increases Threat-Induced Anxiety but Not Fear: Neuroadaptation in Human Addiction

https://doi.org/10.1016/j.biopsych.2010.06.003Get rights and content

Background

Stress response neuroadaptation has been repeatedly implicated in animal addiction models for many drugs, including nicotine. Programmatic laboratory research that examines the stress response of nicotine-deprived humans is necessary to confirm that stress neuroadaptations observed in animal models generalize to humans.

Methods

Two experiments tested the prediction that nicotine deprivation selectively increases startle response associated with anxiety during unpredictable threat but not fear during imminent, predictable threat. Dependent smokers (n = 117) were randomly assigned to 24-hour nicotine-deprived or nondeprived groups and participated in one of two experiments wherein electric shock was administered either unpredictably (noncontingent shock; Experiment 1) or predictably (cue-contingent shock; Experiment 2).

Results

Nicotine deprivation increased overall startle response in Experiment 1, which involved unpredictable administration of shock. Age of first cigarette and years of daily smoking were significant moderators of this deprivation effect. Self-reported withdrawal symptoms also predicted startle response during unpredictable shock. In contrast, nicotine deprivation did not alter overall or fear-potentiated startle in Experiment 2, which involved predictable administration of shock.

Conclusions

These results provide evidence that startle response during unpredictable threat may be a biomarker of stress neuroadaptations among smokers in nicotine withdrawal. Contrast of results across unpredictable versus predictable shock experiments provides preliminary evidence that these stress neuroadaptations manifest selectively as anxiety during unpredictable threat rather than in every stressful context. Individual differences in unpredictable threat startle response associated with withdrawal symptoms, age of first cigarette, and years daily smoking link this laboratory biomarker to clinically relevant indexes of addiction risk and relapse.

Section snippets

Participants

One hundred seventeen chronic smokers aged 18 or older completed one of two separate experiments (Table 1 provides description of participant characteristics). All participants reported ≥10 cigarettes/day ≥1 year, Fagerström Test for Nicotine Dependence (FTND) (21) score ≥4, and expired air carbon monoxide (CO) level ≥10 ppm during screening session. Startle nonresponders (resting startle response during screening session <4 μV) were excluded. All participants were compensated $20/hour for time

Results

Data analysis and figure preparation were accomplished with R (26, 27).

Discussion

Across two experiments, we provide evidence that startle response potentiation during unpredictable threat may be a biomarker of these stress neuroadaptations among human smokers in nicotine withdrawal. In addition, contrast of results for startle response potentiation across unpredictable versus predictable shock experiments provides preliminary evidence that these stress system neuroadaptations manifest selectively as increased anxiety during unpredictable or otherwise uncertain threat.

Limitations and Future Directions

Important limitations of this study will direct our near-term future research. Unpredictable and predictable shock manipulations were implemented in separate experiments because of concerns about carryover of putatively long-lasting anxious affect that precluded counterbalanced, within-subject manipulation. We recognize that this decision limits the strength of conclusions regarding differential nicotine deprivation effects during uncertain versus certain threat. However, the conclusion about a

References (51)

  • G.F. Koob et al.

    Addiction and the brain antireward system

    Annu Rev Psychol

    (2008)
  • Y. Shaham et al.

    The role of neuroadaptations in relapse to drug seeking

    Nat Neurosci

    (2005)
  • F. Weiss et al.

    Compulsive drug-seeking behavior and relapse: neuroadaptation, stress, and conditioning factors

    Ann NY Acad Sci

    (2001)
  • T.B. Baker et al.

    Addiction motivation reformulated: An affective processing model of negative reinforcement

    Psychol Rev

    (2004)
  • M. Davis

    Neural systems involved in fear and anxiety measured with fear-potentiated startle

    Am Psychol

    (2006)
  • M. Davis et al.

    Acoustic startle reflex in rhesus monkeys: a review

    Rev Neurosci

    (2008)
  • C. Grillon

    Models and mechanisms of anxiety: Evidence from startle studies

    Psychopharmacology

    (2008)
  • J.M. Hogle et al.

    Sex differences in negative affect response during nicotine withdrawal

    Psychophysiology

    (2006)
  • C.A. Moberg et al.

    Alcohol selectively reduces anxiety but not fear: Startle response during unpredictable versus predictable threat

    J Abnorm Psychol

    (2009)
  • M. Davis et al.

    Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs. anxiety

    Neuropsychopharmacology

    (2010)
  • N.R. Swerdlow et al.

    Corticotropin-releasing factor potentiates acoustic startle in rats: Blockade by chlordiazepoxide

    Psychopharmacology

    (1986)
  • K.C. Liang et al.

    Corticotropin-releasing factor: Long-lasting facilitation of the acoustic startle reflex

    J Neurosci

    (1992)
  • C. Grillon et al.

    Anxious responses to predictable and unpredictable aversive events

    Behav Neurosci

    (2004)
  • M.E. Piper et al.

    Tobacco withdrawal and negative affect: An analysis of initial emotional response intensity and voluntary emotion regulation

    J Abnorm Psychol

    (2006)
  • A. Geier et al.

    Appetitive nature of drug cues confirmed with physiological measures in a model using pictures of smoking

    Psychopharmacology

    (2000)
  • Cited by (56)

    • Preliminary evidence that reactivity to uncertain threat is an endophenotype for alcohol use disorder

      2017, Drug and Alcohol Dependence
      Citation Excerpt :

      Our AUD groups, however, had higher rates of lifetime SUD and recent substance abuse than the non-AUD groups and although we statistically adjusted for SUD in our analyses, it is possible that the results are not specific to AUD and reflect a broader vulnerability for substance consumption. In fact, other studies have shown that heavy marijuana users (Hefner et al., 2017 unpublished results) and smokers experiencing acute nicotine deprivation (Hogle et al., 2010) display increased startle potentiation to U-threat but not P-threat. It has also recently been argued that heightened reactivity to U-threat reflects a neuroadaptation that emerges as a consequence of drug and alcohol exposure rather than a vulnerability factor (Kaye et al., 2017).

    View all citing articles on Scopus
    View full text