Acute Social Stress Potentiates Cue-Driven Behavior in Alcohol Use Disorder: Behavioral and Neural Evidence

Background: Pavlovian-to-instrumental transfer (PIT) describes how conditioned cues shape instrumentally learned behavior and has been linked to cue-driven alcohol seeking and relapse in alcohol use disorder (AUD). Acute psychosocial stress is an established relapse risk factor that may amplify cue-driven motivational control. Whether acute stress modulates PIT behaviorally and neurally, and whether this differs in AUD, remains unclear. Methods: Within the TRR265 study, 109 participants (62 AUD, 46 controls (CON)) completed a within-subject, randomized, two-day PIT paradigm under Trier Social Stress Test and placebo conditions, with repeated salivary cortisol sampling across sessions. A subsample (n = 62; 34 AUD, 28 CON) underwent fMRI during the transfer phase. Results: A robust PIT effect emerged across groups, and acute stress significantly enhanced cue-driven response vigor (p = .034), with no AUD-specific behavioral effect. Exploratorily, cortisol responders showed stronger stress-related PIT enhancement than non-responders (p = .022). Neurally, PIT engaged the right amygdala during placebo. Acute stress induced less downregulation of PIT-related left amygdala activity in AUD than in CON (pFWE = .019), with no group difference during placebo. Conclusions: Acute psychosocial stress potentiated the motivational influence of non-drug-related conditioned cues on behavior irrespective of AUD status, identifying PIT as a candidate mechanism through which stress may promote alcohol-seeking behavior. Despite comparable behavioral effects, AUD was associated with blunted stress-induced downregulation of PIT-related amygdala activity, suggesting altered neural regulation of cue-driven processing whose relevance for future alcohol consumption and clinical outcome remains to be established.