Vasopressin and angiotensin II pathways differentially modulate human fear response dynamics to looming threats

While basal threat processing dynamics (e.g., visual looming) are well characterized in animals, the underlying mechanisms and their modulation by neuropeptide systems with different modulatory roles in threat processing (vasopressin, angiotensin II) remain poorly understood in humans. In a randomized, placebo-controlled eye-tracking study (N = 111), we administered vasopressin (AVP) or an angiotensin II receptor blocker (via Losartan, LT) during a time-to-collision threat paradigm. This study was prospectively registered at ClinicalTrials.gov (NCT06329076, NCT06329063) on April 11, 2024, prior to participant enrollment. Behaviorally, AVP induced a systematic time overestimation while LT induced temporal compression and reduced state anxiety. Pupillometry revealed distinguishable profiles: AVP induced sustained constriction during stimulus approach followed by post-stimulus threat-specific dilation, LT maintained sustained pupillary constriction throughout both approach and occlusion phases yet preserving threat-specificity, while placebo (PLC) showed no threat-specific modulation. A computational framework (combining Functional Principal Component Analysis, clustering, and Markov chain analysis) underscored the distinct modulations: AVP stabilized a high-arousal state characterized by the co-activation of vigilance, threat-proactive preparation and a shift from perception to internal simulation. LT suppressed transitions to high-arousal states and exhibited maximal sequence entropy, reflecting flexible response patterns-contrasting with placebo's lowest entropy dynamics. These results demonstrate that AVP and LT differentially regulate basal threat processing via separable neuropeptide pathways: AVP sustains hypervigilance while LT promotes anxiolysis and adaptive flexibility. Our findings suggest neuropeptide pathway-specific targets maladaptive threat processing in trauma- or anxiety-related disorders.