Stress effects on mesolimbic dopamine signalling and alcohol cue reactivity in alcohol use disorder: a PET-MR study

Background

Alcohol use disorder (AUD) remains a major global public health concern, characterized by compulsive alcohol use, high relapse risk, and excess mortality, affecting around 5% of the global population. Psychosocial stress represents one of the most potent triggers of acute craving episodes and subsequent relapse events in this prevalent disorder. Despite extensive research, the precise neurobiological mechanisms underlying the interplay between stress-induced alterations in mesolimbic dopamine signalling and enhanced neural responses to alcohol-associated cues remain insufficiently understood. Previous neuroimaging studies have convincingly demonstrated that acute psychosocial stress produces measurable increases in striatal dopamine release [1], while functional magnetic resonance imaging research consistently shows enhanced ventral and dorsal striatal activation in response to alcohol cues among individuals with AUD [2]. Critically however, no previous investigation has successfully conducted simultaneous molecular and functional neuroimaging assessment during acute psychosocial stress exposure to examine their dynamic interaction in this clinical population. This study tests whether experimentally induced psychosocial stress alters striatal dopamine D2/D3 receptor-related binding potential and alcohol cue-induced mesolimbic activation, and whether these changes predict subjective craving and 90-day relapse risk.

Methods

This single-centre, randomised, controlled crossover study planned to enroll 46 adults (aged 30–50 years) with DSM-5 AUD (between 2 to 10 AUD criteria). Participants completed stress and control conditions 7 days apart, counterbalanced for order. Psychosocial stress was induced using the established ScanStress task, adapted for simultaneous 3 Tesla positron emission tomography-magnetic resonance (PET-MR) acquisition, while the control condition omitted time pressure and social-evaluative threat. During session, participants received ~185 MBq [18F]desmethoxyfallypride to quantify transient decreases in striatal binding potential (indexing dopamine release) using the linearised non-invasive PET (lp-ntPET) model with cerebellum reference. A validated alcohol cue-reactivity paradigm (12 alcohol vs 9 neutral picture blocks) with repeated visual analogue scale craving ratings followed immediately. Salivary cortisol was sampled pre- and post-intervention at standardised timepoints. Primary endpoints were within-subject stress-related changes in striatal binding potential and alcohol cue-related blood oxygen level-dependent responses. Preliminary analyses employed mixed-effects models for condition effects and robust bootstrapping for PET-fMRI associations, with striatum as predefined region of interest (pFWE<0.05; Statistical Parametric Mapping 12, PMOD 4.0).

Results

Preliminary data of 10 subjects showed that psychosocial stress was associated with trends toward reduced striatal DMFP binding potential and increased alcohol cue-induced striatal activation compared to control conditions. Recruitment and data collection continue across both experimental conditions.

Conclusions

This study establishes a feasible multimodal framework integrating molecular imaging, functional neuroimaging, neuroendocrine, and behavioural measures to investigate whether psychosocial stress modulates mesolimbic dopamine signalling and alcohol cue reactivity in AUD. Preliminary findings support the primary hypotheses and warrant confirmation through full-sample analyses, potentially clarifying neurobiological pathways linking acute stress exposure to craving vulnerability and relapse risk. These insights may ultimately inform novel pharmacotherapeutic and psychotherapeutic strategies targeting stress-dopamine interactions to improve clinical outcomes in AUD.

References

1. Pruessner JC, et al., 2004. Dopamine release in response to a psychological stress in humans. Journal of Neuroscience 24, 2825-2831.
2. Grusser, S.M., et al., 2004. Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics. Psychopharmacology 175, 296-302.