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. Work in animals implicates the central extended amygdala (EAc), but the translational relevance of these discoveries remains speculative. 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.

Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis

“…F(1,64)=18.18, p<0.001, pη 2 =0.22). These observations are broadly consistent with prior work using shock-reinforced threat-anticipation tasks in adults and reinforce the validity of the MSTC paradigm for probing social anxiety in adolescence(Grogans et al, under review;Hur et al, 2020;Kim et al, 2023).The EAc is preferentially engaged by the anticipation of temporally uncertain social threat We leveraged anatomically defined Ce and BST ROIs and spatially unsmoothed fMRI data to test whether more severe social-anxiety symptoms are associated with exaggerated EAc activation when anticipating encounters with social threat, and to explore the possibility that threat-potentiation depends on the temporal certainty of encounters. A mixed-effects GLM revealed significant effects of Region, reflecting greater anticipatory activation, on average, in the Ce compared to the BST (F(differ from one another (t(64)=-0.39, p=0.70).…”

“…Anatomical Data Processing. Methods are similar to those described in other recent reports by our group (Grogans et al, under review;Hur et al, 2018;Hur et al, 2022;Hur et al, 2020;Kim et al, 2023).…”

“…Items probe the frequency of fear or anxiety symptoms evoked by specific social situations (e.g., "I feel scared when I have to speak or read in front of a group of people") on a 3-point Likert scale ranging from 0 Hur et al, 2022;Hur et al, 2020;Kim et al, 2023), the MSTC paradigm takes the form of a 2 (Valence: Social Threat/Safety) × 2 (Temporal Certainty: Uncertain/Certain) × 2 (Phase:…”

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala

“…The paradigm has been successfully deployed in university students and community volunteers (Hur et al, 2020b;Hur et al, 2022;Kim et al, 2023).…”

“…Hypothesis testing focused on anatomically defined EAc regions of interest (ROIs), as detailed below. To maximize anatomical resolution, no additional spatial filters were applied, consistent with prior work by our team and recent recommendations (Tillman et al, 2018;Kim et al, 2023).…”