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Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

ABSTRACT: Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

SUBMITTER: Kim HC

PROVIDER: S-EPMC10358993 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Kim Hyung Cho HC Kaplan Claire M CM Islam Samiha S Anderson Allegra S AS Piper Megan E ME Bradford Daniel E DE Curtin John J JJ DeYoung Kathryn A KA Smith Jason F JF Fox Andrew S AS Shackman Alexander J AJ

PloS one 20230720 7

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the ...[more]

PMID: 37471317

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Project description:BackgroundStress 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.MethodsTwo 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).ResultsNicotine 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.ConclusionsThese 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.

Project description:IntroductionAlthough exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence.Aims and methodsThirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration.ResultsNo main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046).ConclusionsProgesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking.ImplicationsIn male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence.Clinicaltrials.gov registrationNCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Dataset Information

Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Publications

Acute nicotine abstinence amplifies subjective withdrawal symptoms and threat-evoked fear and anxiety, but not extended amygdala reactivity.

Similar Datasets

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