Intrusive memories are a core symptom of posttraumatic stress disorder (PTSD), a mental disorder with a high risk for chronic progression, psychological and physical comorbidities and socio-functional impairments. Despite extensive research, the mechanisms underlying the development of PTSD following trauma exposure remain insufficiently understood. There is increasing evidence that neuroendocrine stress systems, such as the hypothalamic-pituitary- adrenal (HPA) axis and the noradrenergic system, play a role in the formation of intrusive memories. Beyond that, the oxytocin system, known for its involvement in stress regulation and social behavior, has emerged as a promising candidate for PTSD prevention research. However, findings regarding its effects on memory and stress remain inconclusive and appear to depend on individual and contextual factors. Oxytocin’s effects seem to be closely intertwined with endocrine stress system activity, suggesting that variations in physiological stress states may shape its impact. The use of oral contraceptives (OCs), which alter endocrine functioning, is gaining recognition as a relevant, yet underexplored, factor in both oxytocin-related and PTSD research. The primary aim of this dissertation is to investigate whether and how exogenous oxytocin influences the formation of intrusive (involuntary) memories after a trauma paradigm in healthy women. A secondary aim is to examine the moderating role of neuroendocrine stress markers, genetic factors, and OC use on oxytocin’s effects. In addition, the dissertation explores oxytocin’s influence on voluntary trauma-related memory. To address these questions, four experimental studies using a validated trauma film paradigm in healthy women were conducted. Study I examined whether the administration of oxytocin after trauma exposure—during the consolidation phase—affects the development of intrusive memories. Study II investigated the effects of oxytocin administration before trauma exposure, mainly targeting the memory acquisition phase. In both studies, potential moderating effects of individual differences in cortisol (as an indicator of HPA axis activity), salivary alpha-amylase (sAA; as a marker of noradrenergic activity), heart rate variability (HRV; reflecting autonomic nervous system regulation), and genetic variations on the oxytocin effect were explored. Study III investigated whether the use of OCs impacts oxytocin’s effects on the development of intrusive memories and whether OCs independently influence the development of intrusive memories. Study IV examined whether oxytocin administration before or after trauma exposure influences voluntary recognition memory for trauma-related content. The main findings are as follows: Oxytocin did not exert a general dampening effect on intrusive memories. Rather, its impact was modulated by timing and individual physiological profiles. While the administration of oxytocin after a trauma paradigm (Study I) did not influence the subsequent development of intrusive memories, the administration of oxytocin before a trauma paradigm (Study II) increased intrusive memories in the aftermath. This effect was influenced by baseline cortisol, HRV, and genetic variation, including polygenic risk scores for PTSD and the single nucleotide polymorphism rs53576 in the oxytocin receptor gene. OC use did not affect the impact of oxytocin on intrusive memories. However, participants using OCs showed a blunted decline in intrusive memories after the trauma film compared to naturally cycling women (Study III). Voluntary recognition memory was unaffected by oxytocin administration, whether given before or after the trauma film (Study IV). In conclusion, the trauma film paradigm enabled a controlled investigation of processes that cannot be studied during real-life trauma exposure. This dissertation provides novel insights into the role of oxytocin in trauma-related memory formation and underscores the importance of accounting for neuroendocrine and genetic moderators (i.e., cortisol, HRV and genetic variations) when examining oxytocin in the context of PTSD. Notably, the findings suggest that oxytocin administration prior to trauma exposure may be contraindicated, as it was associated with an increase in intrusive memories, particularly in individuals with certain physiological profiles. In contrast, no effects were observed for oxytocin administration after trauma exposure; however, this absence of effect may be attributable to methodological factors, such as timing, dosage, or the nature of the trauma analogue. By integrating the biological moderators assessed in this dissertation into existing models of PTSD, the findings offer promising directions for the development of targeted, individualized prevention strategies. Although not the primary focus of this dissertation, the results also point to OC use as a biologically relevant variable that may influence trauma-related memory processes and should therefore be considered in both future research and clinical practice.
