Based on work by Nicholson and colleagues, the directionality of connectivity of key brain regions implicated in emotional responding among individuals with PTSD and PTSD+DS is elucidated. PTSD (left side of image) is characterized by predominant bottom-up connectivity from the peraqueductal gray (PAG) to the bilateral centromedial amygdala (CMA) and from the BLA to the vmPFC suggesting defensive responding driven by mibrain and limbic regions and chronic fear responses. In contrast, PTSD+DS (right side of image) is characterized by predominant top-down connectivity between the bilateral CMA and PAG and vmPFC with the BLA, consistent with chronic emotional overmodulation and detachment from emotional responses associated with symptoms of depersonalization and derealization

Based on work by Nicholson and colleagues, the directionality of connectivity of key brain regions implicated in emotional responding among individuals with PTSD and PTSD+DS is elucidated. PTSD (left side of image) is characterized by predominant bottom-up connectivity from the peraqueductal gray (PAG) to the bilateral centromedial amygdala (CMA) and from the BLA to the vmPFC suggesting defensive responding driven by mibrain and limbic regions and chronic fear responses. In contrast, PTSD+DS (right side of image) is characterized by predominant top-down connectivity between the bilateral CMA and PAG and vmPFC with the BLA, consistent with chronic emotional overmodulation and detachment from emotional responses associated with symptoms of depersonalization and derealization

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Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non...

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Prenatal ethanol exposure (PEE) promotes ethanol consumption in the adolescent offspring accompanied by the transcriptional regulation of kappa opioid receptor (KOR) system genes. This study analysed if environmental enrichment (EE, from gestational day 20 to postnatal day 26) exerts protective effects upon PEE-modulation of gene expression, ethano...

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... Brain imaging studies on dissociative disorders have focused on two issues: the brain imaging correlates of dissociation per se , and the brain imaging diff erences between dissociative patients and normal controls (or other psychiatric patients). Signifi cant brain-imaging diff erences have been found between (a) diff erent types of dissociative parts of the patient's personality in DID patients (Reinders, Nijenhuis, Paans, Korf, Willemsen, & Den Boer, 2006 ; see Nijenhuis,Chapter 38 ,and Lebois et al.,Chapter 24 ,this volume), (b) dissociative responses and nondissociative responses to trauma-related scripts as elements of PTSD patients' responses to triggers (Lanius, Williamson, Boksman, Densmore, Gupta, Neufeld, Gati, & Menon, 2002 ;see Schiavone & Lanius, Chapter 39 , this volume) including comparisons of the dissociative subtype to other types of PTSD (Lanius et al., 2018 ); (c) perfusion before versus perfusion during switching in DID patients ( Tsai, Condie, Wu, & Chang, 1999 ;Savoy et al., 2012 ); and (d) the cerebral perfusion of dissociative patients versus that of normal controls ( Ş ar, Ü nal, K ı z ı ltan, Kundak çı , & Ö zt ü rk, 2001 ; Ş ar, Ü nal, & Ö zt ü rk, 2007 ). ...
... Despite its potential implications, this perspective has not been specifi cally addressed in subsequent neurobiological studies on DID. Lanius et al. (2018) hypothesized that kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotional overmodulation in the dissociative subtype of PTSD. Conversely, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fi ght or fl ight components of the defense cascade. ...
Chapter
This chapter explores the most pertinent research questions to understand and advance the study of dissociation. Drawing on specifi c themes, recommendations for future work are outlined at the end of each section. Our chapter in the fi rst edition of this book still contains questions empirically unanswered (e.g., genetics and neurobiology of dissociative disorders, dissociation in other psychiatric disorders). We will focus in this chapter on the most pressing questions that currently need to inform the scientifi c understanding of dissociation.
... A recent meta-analysis of studies on electrodermal activity concluded that patients with DPD exhibit high levels of sympathetic arousal (reflecting hypervigilance) but reduced skin conductance (reflecting attenuated emotional response) in response to unpleasant stimuli (Horn et al., 2020). Likewise, emotional numbing and suppression of neural activity in regions associated with emotional responding to threat are implicated in etiological models of dissociative disorders more broadly (Frewen & Lanius, 2014;Lanius et al., 2018). The Nonreactivity facet of the FFMQ may thus partially capture this involuntary emotional numbing among individuals who suffer from depersonalization symptoms. ...
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Objectives Although depersonalization has been described as the antithesis of mindfulness, few studies have empirically examined this relationship, and none have considered how it may differ across various facets of mindfulness, either alone or in interaction. The present study examined the relationship between symptoms of depersonalization and facets of dispositional mindfulness in a general population sample. Methods A total of 296 adult participants (139 male, 155 female, 2 other) were recruited online via Qualtrics and completed the Cambridge Depersonalisation Scale; Depression, Anxiety, and Stress Scale; and Five Facet Mindfulness Questionnaire. Results Controlling for general distress, depersonalization symptoms were positively associated with Observe, Describe, and Nonreactivity facets and negatively associated with Acting with Awareness and Nonjudgment facets. After controlling for intercorrelations among the facets, depersonalization symptoms remained significantly associated with higher Nonreactivity and lower Acting with Awareness. The overall positive relationship between depersonalization symptoms and the Observe facet was moderated by both Nonjudgment and Nonreactivity. Specifically, higher Observing was related to increased depersonalization symptoms at low levels of Nonjudgment and to decreased symptoms at low levels of Nonreactivity. Conclusions The current study provides novel insight into the relationship between depersonalization symptoms and various aspects of mindfulness. Experiences of depersonalization demonstrated divergent relationships with mindfulness facets, alone and in interaction. The results may inform theoretical models of depersonalization and mindfulness-based interventions for depersonalization.
... Arousal is critical to the conceptualization of posttraumatic stress disorder (PTSD) since it is a dynamic disorder that includes arousal states ranging from hyperarousal (e.g., hypervigilance, altered startle threshold) to more blunted arousal patterns associated with emotional detachment, depersonalization, and derealization. These latter states are more frequently associated with the dissociative subtype of PTSD (PTSD + DS) (Wolf et al., 2012a,b;APA, 2013;Seligowski et al., 2019; for review see Hansen et al., 2017;Fenster et al., 2018;Lanius et al., 2018;van Huijstee and Vermetten, 2018). ...
... On a neural level, hyperarousal states have been found to be associated with reduced activation of brain regions underlying cognitive control (e.g., ventromedial prefrontal cortex) and enhanced activation of brain regions underlying emotion generation (e.g., amygdala, periaqueductal gray), while the reverse pattern has been implicated in more blunted arousal states (e.g., Fenster et al., 2018;Lanius et al., 2018; see also Lebois et al., 2021). Critically, the aforementioned interaction profile between subcortical and cortical brain regions has recently been extended to include deep-layer brain regions involved in arousal and innate reflexive function (Harricharan et al., 2016; see also Holmes et al., 2018;Olive et al., 2018;Rabellino et al., 2018aRabellino et al., , 2019Brandão and Lovick, 2019;Terpou et al., 2019bTerpou et al., , 2020Terpou et al., , 2022Thome et al., 2019;Haubrich et al., 2020;Lanius et al., 2020;Webb et al., 2020). ...
... Indeed, prior investigations have demonstrated a positive relationship between parasympathetic nervous system (PNS) activity and dissociation in response to threatening cues in other clinical populations, thus pointing to a close relationship between sympathoinhibition and dissociative symptomatology (Farina et al., 2015;Fitzpatrick and Kuo, 2015;Chou et al., 2018;Schäflein et al., 2018;Krause-Utz et al., 2019). Specifically, dissociation has been associated with parasympathetic overactivation, which has been thought to be linked to emotional detachment as expressed by symptoms of emotional numbing, depersonalization, and derealization (for an overview see Schauer and Elbert, 2015;Lanius et al., 2018Lanius et al., , 2020Terpou et al., 2019b). ...
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Background Increasing evidence points toward the need to extend the neurobiological conceptualization of posttraumatic stress disorder (PTSD) to include evolutionarily conserved neurocircuitries centered on the brainstem and the midbrain. The reticular activating system (RAS) helps to shape the arousal state of the brain, acting as a bridge between brain and body. To modulate arousal, the RAS is closely tied to the autonomic nervous system (ANS). Individuals with PTSD often reveal altered arousal patterns, ranging from hyper- to blunted arousal states, as well as altered functional connectivity profiles of key arousal-related brain structures that receive direct projections from the RAS. Accordingly, the present study aims to explore resting state functional connectivity of the RAS and its interaction with the ANS in participants with PTSD and its dissociative subtype. Methods Individuals with PTSD ( n = 57), its dissociative subtype (PTSD + DS, n = 32) and healthy controls ( n = 40) underwent a 6-min resting functional magnetic resonance imaging and pulse data recording. Resting state functional connectivity (rsFC) of a central node of the RAS – the pedunculopontine nuclei (PPN) – was investigated along with its relation to ANS functioning as indexed by heart rate variability (HRV). HRV is a prominent marker indexing the flexibility of an organism to react adaptively to environmental needs, with higher HRV representing greater effective adaptation. Results Both PTSD and PTSD + DS demonstrated reduced HRV as compared to controls. HRV measures were then correlated with rsFC of the PPN. Critically, participants with PTSD and participants with PTSD + DS displayed inverse correlations between HRV and rsFC between the PPN and key limbic structures, including the amygdala. Whereas participants with PTSD displayed a positive relationship between HRV and PPN rsFC with the amygdala, participants with PTSD + DS demonstrated a negative relationship between HRV and PPN rsFC with the amygdala. Conclusion The present exploratory investigation reveals contrasting patterns of arousal-related circuitry among participants with PTSD and PTSD + DS, providing a neurobiological lens to interpret hyper- and more blunted arousal states in PTSD and PTSD + DS, respectively.
... As such, multiple investigations have found that symptoms of dissociation are frequently reported, and even distinctly elevated among those who have experienced betrayal trauma, as opposed to other types of trauma (Goldsmith et al., 2012;Hulette et al., 2011;Tang & Freyd, 2012). Dissociation is part of the freeze response to danger, marked by physiological hypoarousal and emotional overmodulation (Lanius et al., 2018). Dissociation is thought to serve a uniquely protective function in the context of betrayal trauma, as it allows a young victim to maintain an attachment relationship with a caregiver upon whom they are dependent by attenuating the youth's awareness of caregiver threat (Freyd, 1994(Freyd, , 1996Gagnon et al., 2017). ...
... Dissociative symptoms are "characterized by a disruption of and/or discontinuity in the normal integration of consciousness, memory, identity, emotional, perception, body representation, motor control, and behavior" (American Psychiatric Association, 2013, p. 291). Dissociation can contribute to a state of emotional overmodulation/inhibition, which can alter threat detection, thereby increasing one's own vulnerability for subsequent revictimization, as well as their vulnerability of their child (Lanius et al., 2018;Tschoeke et al., 2019).Studies by Chu and DePrince (2006) and Hulette et al. (2011) have both found statistically significant associations between histories of maternal betrayal trauma and maternal dissociation, which is known to negatively impact parenting behaviors, potentially resulting in overall reduced maternal availability, specifically in the areas of maternal sensitivity and non-intrusiveness (Williams et al., 2021). Additionally, Hulette et al. (2011) reported unique links between maternal exposure to betrayal trauma during childhood and subsequent interpersonal revictimization among the mothers during adulthood, which also amplified dissociative symptoms. ...
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Betrayal trauma is associated with dissociative symptoms, which can increase the risk of suicidal thoughts and behaviors. Previous research demonstrates associations between a mother’s history of betrayal trauma and intergenerational patterns of maltreatment and dissociation among their children. However, maternal betrayal trauma history remains unexplored in the etiology of youth suicidality. This study was conducted to investigate pathways between maternal betrayal trauma and youth suicidality, while considering the influences of youth maltreatment exposure and symptoms of dissociation. We implemented conditional growth curve modeling in a structural equation modeling framework to analyze secondary data from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN; N = 1,354; 51.48% female, 53.29% Black). Predictors included mothers’ betrayal trauma history, youth maltreatment exposure, and youth dissociative symptoms at ages 8, 12, and 16. The slope and intercept of dissociative symptoms at the age-8, age-12, and age-16 visit were modeled as latent factors. A robust weighted least squares estimator accounted for categorical outcomes. Indirect effects were assessed via the delta method. We found a significant indirect effect from maternal betrayal trauma to adolescent suicidal ideation through children’s maltreatment exposure and the growth in children’s dissociative symptoms from ages 8 through 16. Maternal betrayal trauma may play a unique role in perpetuating intergenerational patterns of trauma that contribute to subsequent trajectories of youth suicidality among their offspring. Practice implications for screening, prevention, and early intervention strategies are described, along with directions for further study.
... In this review, we thus focus on both preclinical and clinical research related to the modulation of the KOR system, and its endogenous ligand dynorphin (DYN), in relation with stress and addiction. The interest for this topic has been growing recently (Helal et al., 2017;Karkhanis et al., 2017;Jacobson et al., 2018;Lanius et al., 2018;Valentino and Volkow, 2018;Beck et al., 2019;Margolis and Karkhanis, 2019;Tejeda and Bonci, 2019;Anderson, 2020;Escobar et al., 2020;Nagase and Saitoh, 2020). We will thus list here some of the most relevant literature on the DYN/KOR system in pain, dysphoria and psychiatric disorders. ...
... Stress-induced analgesia is KOR dependent in the case of inescapable stress. This may somehow be related to dissociative states, following an emotional shutdown, thought to involve KOR activation, increasing opioid dependent analgesia and producing alterations of mood and perception (Lanius et al., 2018). CRF, Corticotropin Releasing Factor; DA, dopamine; HPA axis, Hypothalamo-Pituitary-Adrenal axis; KOR, Kappa Opioid Receptor; VTA, ventral Tegmental Area. the risk of adverse effects. ...
... Interestingly, because of its dysphoric and aversive effects, the KOR system was argued to contribute to the negative affective states induced by pain, driving mood-related pathologies associated with chronic pain (Cahill et al., 2014). Furthermore, in humans, KOR agonists could produce a dissociative-like syndrome, a state occurring during an inescapable traumatic experience (Lanius et al., 2018). These dysphoric effects are thought to be the consequence of a dopamine (DA) depletion in the reward and the fear circuits (Karkhanis et al., 2017;Lanius et al., 2018;Escobar et al., 2020). ...
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Substance use disorders (SUD) may emerge from an individual’s attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity.
... The authors postulated that unpleasant visceral sensations aroused when recalling morally injurious events may, in turn, lead to increased activation of modulating brain areas such as the dorsolateral prefrontal cortex, or the central executive network, in an effort to control excessive bottom-up activity evoked from recalling morally injurious events (83). Critically, over-modulation of excessive bottom-up affect is a pattern of neural activation consistent with dissociation (82,83). Social support, for example, may then be an important factor in processing morally injurious events as treatments focused on bottom-up affective processes and bodily sensation may encourage prosocial, attachment-based, interpersonal relationships and in turn alleviate interfering symptoms, including heightened arousal and dissociation. ...
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The COVID-19 pandemic has resulted in a still-unfolding series of novel, potentially traumatic moral and ethical challenges that place many healthcare workers at risk of developing moral injury. Moral injury is a type of psychological response that may arise when one transgresses or witnesses another transgress deeply held moral values, or when one feels that an individual or institution that has a duty to provide care has failed to do so. Despite knowledge of this widespread exposure, to date, empirical data are scarce as to how to prevent and, where necessary, treat COVID-19-related moral injury in healthcare workers. Given the relation between moral injury and post-traumatic stress disorder (PTSD), we point here to social and interpersonal factors as critical moderators of PTSD symptomology and consider how this knowledge may translate to interventions for COVID-19-related moral injury. Specifically, we first review alterations in social cognitive functioning observed among individuals with PTSD that may give rise to interpersonal difficulties. Drawing on Nietlisbach and Maercker's 2009 work on interpersonal factors relevant to survivors of trauma with PTSD, we then review the role of perceived social support, social acknowledgment and social exclusion in relation to potential areas of targeted intervention for COVID-19-related moral injury in healthcare workers. Finally, building on existing literature (e.g., Phoenix Australia—Centre for Posttraumatic Mental Health and the Canadian Centre of Excellence—PTSD, 2020) we conclude with individual and organizational considerations to bolster against the development of moral injury in healthcare workers during the pandemic.
... Studies focused on measures of trait dissociation, rather than measuring state dissociation, which may have resulted in underestimation of the impact of dissociative processes during NSSI (Brand et al., 2009). Both dissociation and NSSI have been associated with opioid release and altered pain perception, potentially implicating the opioid system (Lanius et al., 2018). Kleindienst et al. (2008) reported BPD participants who did not feel pain during NSSI scored very high on the DES (mean = 43.6 [SD = 19.2]) ...
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Background Borderline Personality Disorder (BPD) is frequently complicated by the presence of dissociative symptoms. Pathological dissociation is linked with earlier and more severe trauma exposure, emotional dysregulation and worse treatment outcomes in Posttraumatic Stress Disorder and Dissociative Disorders, with implications for BPD. Objective A systematic scoping review was conducted to assess the extent of current literature regarding the impact of dissociation on BPD and to identify knowledge gaps. Methods Four electronic databases (MEDLINE, APA PsycINFO, EMBASE, CINAHL Plus) were searched, and English peer-reviewed studies with adults with BPD were included, following Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) extension for scoping reviews (PRISMA-ScR) 2018 guidelines. Results Most of the 70 included studies were observational (98%) with first authors from Germany (59%). Overall, dissociation was associated with increased BPD symptom severity, self-harm and reduced psychotherapy treatment response; findings regarding suicide risk were mixed. Dissociation was associated with working memory and cognitive deficits, decreased pain perception, altered body ownership, no substance abuse or the abuse of sedative substances, increased fantasy proneness, personality fragmentation, fearful attachment, dream anxiety, perceived stress and altered stress responses, increased cumulative body mass index, decreased water consumption, several neurological correlates and changes in gene expression. Conclusion BPD with significant dissociative symptoms may constitute a more severe and at-risk subgroup of BPD patients. However, there are significant research gaps and methodological issues in the area, including the possibility of unrecognized Dissociative Disorders in BPD study populations confounding results. Further studies are needed to better understand the impact of dissociation on BPD course and treatment, and to clarify the most appropriate assessment tools for clinical practice. In addition, interventional studies are needed to develop dissociation-specific BPD treatments to determine whether targeting dissociation in BPD can improve treatment outcomes.
... The idea was simple: researchers asked participants to narrate their traumatic experiences and then played back these recordings during the scan; the researchers could then acquire measures of brain activity while the individuals were actively symptomatic. Early data were incredibly encouraging-as expected, they showed increased autonomic arousal and hyperactive amygdala activity (4,5). This matched many patients' subjective reports of hyperarousal and reactivity. ...
... 128 The latest studies about dissociative process showed the importance of prefrontal cortex and subcortical structures (amygdala, periaqueductal grey) for sustaining the detection of fear and its behavioural and autonomic response. 129 For instance, in subjects with PTSD and dissociative symptoms, top-down modulation of the subcortical regions by the prefrontal cortex would be increased leading to a passive defensive response such as unresponsive immobility and emotional detachment (associated with derealisation/depersonalisation). 129 According to animal models, this passive defensive response would be sustained by the parasympathetic and endogenous opioid systems. ...
... 129 For instance, in subjects with PTSD and dissociative symptoms, top-down modulation of the subcortical regions by the prefrontal cortex would be increased leading to a passive defensive response such as unresponsive immobility and emotional detachment (associated with derealisation/depersonalisation). 129 According to animal models, this passive defensive response would be sustained by the parasympathetic and endogenous opioid systems. 129 The overactivation of kappa-opioid receptors, secondary to trauma exposure, would play a role in experiencing altered consciousness. ...
... 129 According to animal models, this passive defensive response would be sustained by the parasympathetic and endogenous opioid systems. 129 The overactivation of kappa-opioid receptors, secondary to trauma exposure, would play a role in experiencing altered consciousness. 129 ...
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Functional seizures (FS) known also as psychogenic non-epileptic seizures or dissociative seizures, present with ictal semiological manifestations, along with various comorbid neurological and psychological disorders. Terminology inconsistencies and discrepancies in nomenclatures of FS may reflect limitations in understanding the neuropsychiatric intricacies of this disorder. Psychological and neurobiological processes of FS are incompletely understood. Nevertheless, important advances have been made on underlying neuropsychopathophysiological mechanisms of FS. These advances provide valuable information about the underlying mechanisms of mind–body interactions. From this perspective, this narrative review summarises recent studies about aetiopathogenesis of FS at two levels: possible risk factors (why) and different aetiopathogenic models of FS (how). We divided possible risk factors for FS into three categories, namely neurobiological, psychological and cognitive risk factors. We also presented different models of FS based on psychological and neuroanatomical understanding, multilevel models and integrative understanding of FS. This work should help professionals to better understand current views on the multifactorial mechanisms involved in the development of FS. Shedding light on the different FS profiles in terms of aetiopathogenesis will help guide how best to direct therapy, based on these different underlying mechanisms.
... The FST was originally developed as a screening test for antidepressants, and its mechanistic underpinnings and interpretation have been extensively discussed (Porsolt et al., 1977;Porsolt et al.,1978;Chen et al., 2015;Molendijk and de Kloet, 2019;Armario, 2021). Recent reviews conclude that increased immobility in swim stress assays is reflective of a transition from active to passive coping, in the face of an inescapable stressor (Lanius et al., 2018;Molendijk and de Kloet, 2019;Armario, 2021). Several authors have also found that greater swim area allows more adaptive swimming behaviors for study (Jacobson M. L. et al., 2020;Armario, 2021). ...
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The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo . A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (<3 h) of KOR-antagonist effects, based on its blockade of the locomotor depressant effects of the KOR-agonist U50,488 (10 mg/kg). LY2795050 (0.32 mg/kg), when administered only 1 min prior to the OSS stress paradigm, decreased immobility in males, but not females. With a slightly longer pretreatment time (15 min), this dose of LY2795050 decreased immobility in both males and females. A 10-fold smaller dose of LY2795050 (0.032 mg/kg) was inactive in the OSS, showing dose-dependence of this anti-stress effect. Overall, these studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure.