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. 2010 Oct 15;68(8):719-25.
doi: 10.1016/j.biopsych.2010.06.003. Epub 2010 Jul 31.

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

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

Joanne M Hogle et al. Biol Psychiatry. .
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Abstract

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.

Figures

Figure 1
Figure 1
Neutral Baseline Startle Response by Deprivation Group and Probe Number. Baseline startle response was measured to 9 acoustic probes presented during the neutral baseline that preceded the experimental task. Normal habituation of the startle response was observed across probes. No significant Deprivation Group differences were observed for either habituation or mean level of the startle response during this baseline procedure. Error bars represent the standard errors for the point estimates from the General Linear Model.
Figure 2
Figure 2
Startle Response during Unpredictable Shock by Deprivation Group and Cue Type. Electric shocks were administered unpredictably at any point in the task in Experiment 1. Deprived smokers displayed significantly increased startle response during CUE+, CUE− and the inter-trial interval (ITI) relative to non-deprived smokers when shocks were administered unpredictably. Error bars represent the standard errors for the point estimates from the General Linear Model. * p ≤ .05, ** p ≤ .01, *** p ≤ .001
Figure 3
Figure 3
Age of First Cigarette and Years Daily Smoking moderate Deprivation Group effect during Unpredictable Shock. Left panel: Participants’ age when they smoked their first cigarette significantly moderated the magnitude of the Deprivation Group effect on startle response during unpredictable shock in Experiment 1. The Deprivation group effect was largest among participants who reported early cigarette use consistent with their putative increased vulnerability for addiction. The Deprivation Group effect decreased by 7.6 μV for every year older the participant reported first cigarette use. Gray lines represent the standard errors for the point estimates from the General Linear Model. Right panel: Participants’ years of daily cigarette use significantly moderated the magnitude of the Deprivation Group effect on startle response during unpredictable shock in Experiment 1. The Deprivation group effect was largest among participants who reported fewer years of daily cigarette use. The Deprivation Group effect decreased by 1.8 μV for every year of daily cigarette use reported by the participant, suggesting that long term chronic use may be sufficient to increase anxiety even without substantial nicotine deprivation. Gray lines represent the standard errors for the point estimates from the General Linear Model.
Figure 4
Figure 4
Startle Response during Predictable Shock by Deprivation Group and Cue Type. Electric shocks were administered predictably only during CUE+ trials in the task in Experiment 2. All participants displayed significant Fear-potentiated startle (FPS, startle potentiation during CUE+ relative to CUE− trials and the ITI). However, Deprivation Group did not moderate FPS magnitude, indicating comparable fear response to predictable shocks among deprived and non-deprived smokers. Furthermore, deprived and non-deprived smokers did not differ significantly in their overall startle response (across cues) during the predictable shock task. Error bars represent the standard errors for the point estimates from the General Linear Model. * p ≤ .05, ** p ≤ .01, *** p ≤ .001

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