HPA Axis Response Research Articles

Pre-treatment cortisol awakening response predicts symptom reduction in posttraumatic stress disorder after treatment

Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N=41) and non-PTSD (N=25) combat-exposed male subjects. Measurements took place at inclusion and 6–8 months after inclusion for both the PTSD and the non-PTSD group. During the 6–8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD.

Emotion socialization as a predictor of physiological and psychological responses to stress

Reactivity patterns to acute stress are important indicators of physical and mental health. However, the relationships between emotion socialization and stress responses are not well understood. This study aimed to examine whether parental responses to negative emotions predicted physiological and psychological responses to acute stress in late adolescence and emerging adulthood, and whether these relationships varied by gender and ethnicity. Participants were 973 individuals (mean age=19.20years; 50% male; 63% African American, 34% European American) who reported on parental emotion socialization. Participants completed a standardized social stress test (the Trier Social Stress Test; TSST). Heart rate, blood pressure and salivary samples were assessed from baseline throughout the task and during recovery period. Psychological responses to stress were measured immediately after the TSST. Unsupportive parental responses to children's negative emotions were associated with blunted cortisol reactivity and greater negative emotions to a psychosocial stress task in females and African American youth, whereas supportive parental responses predicted greater cortisol reactivity and lower negative emotions to stress in European American youth, as well as less negative emotions in males. However, parental responses to negative emotions did not predict heart rate or SBP reactivity to the TSST. Findings suggest that parental emotion socialization may be an important factor influencing HPA axis reactivity and psychological responses to stress, with important differences across gender and ethnic youth subgroups.

Tu1627 - Resilience is Associated with Early Life Stress and HPA Axis Response in IBS

Tu1627 - Resilience is Associated with Early Life Stress and HPA Axis Response in IBS

Stress and the serotonergic system, observations from pet imaging

IntroductionStress response and the neuroendocrinologic factors through which it is mediated are disturbed in anxiety and in affective disorders. While acute stress is thought to result in hypothalamus-pituitary-adrenal- (HPA) axis hyperactivity (Varghese 2001), chronic stress may result in decreased HPA-response (Booji 2013). Antidepressant treatment, on the other hand, is thought to realign HPA–axis activity (Schüle 2007).On the other hand, dysregulation within the serotonergic neurotransmitter system is understood as a central moderator in the pathophysiology of affective and anxiety disorders. Serotonergic transmission both regulates- and is regulated by- glucocortocoids. Cortisol results in an increase in serotonin synthesis and release while serotonergic transmission is thought to downregulate HPA-axis activity (Lanfumey, 2008). Positron emission tomography (PET) studies have demonstrated the link between the serotonergic system and the HPA-axis in humans in vivo. For example, a negative correlation between cortisol and 5HT1A receptor levels in various brain regions has been shown (Lanzenberger, 2010). SERT expression, on the other hand, was shown using PET to be positively related to HPA-axis reactivity (Frokjaer 2013).Methodsn.a.AimsAvailable literature on interactions between the HPA-axis and the serotonergic system will be discussed with a focus on data acquired via PET studies.Resultsn.a.ConclusionsThe interaction between the serotonergic system and the HPA-axis is likely bilateral and may be understood as a neurobiological link by which stress may foster the development of depression and anxiety.Disclosure of interestM. Spies has received travel grants from AOP Orphan Pharmaceuticals AG, Janssen-Cilag Pharma Gmbh, and Eli Lilly, workshop participation from Eli Lilly, and speaker honoraria from Janssen-Cilag Pharma Gmbh. R. Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, Roche Austria GmbH, Dr. Willmar Schwabe GmbH & Co. KG, AOP Orphan Pharmaceuticals, and Janssen-Cilag Pharma Gmbh.

HPA-Axis Activation as a Key Moderator of Childhood Trauma Exposure and Adolescent Mental Health.

Individual differences in a child's sensitivity to stress may influence whether youth exposed to trauma develop symptoms of psychopathology. We examined the interaction between HPA-axis reactivity to an acute stressor and exposure to different types of childhood trauma as predictors of mental health symptoms in a sample of youth. Youth (n = 121, ages 9-16; 47% female) completed a standardized stress task, including 5 post-stress salivary cortisol samples. Parents also completed the Child Behavior Checklist as a measure of child internalizing and externalizing symptoms in the past month, and completed the Early Trauma Inventory (ETI) as a measure of their child's trauma exposure. More emotional abuse and non-intentional trauma were associated with greater internalizing symptoms. Youth exposed to physical abuse who demonstrated slower HPA-axis reactivity had elevated internalizing and externalizing symptoms. Youth exposed to emotional abuse or non-intentional traumatic events who demonstrated faster HPA-axis reactivity had elevated internalizing and externalizing symptoms. Profiles of exaggerated or attenuated HPA-axis reactivity to acute stress may be risk factors for psychopathology in children facing different stressful social environments.

The psychology of HPA axis activation: Examining subjective emotional distress and control in a phobic fear exposure model

The HPA axis plays a key role in mediating the effects of “stress” on health, but clarifying mechanisms requires an understanding of psycho-biological linkages. There has long been an implicit assumption that subjective emotional distress (e.g., fear) should activate the HPA axis. Although this assumption was challenged 25 years ago (Curtis, 1976), laboratory studies in humans are limited. In this study we sought to replicate Curtis‘ findings and extend it by investigating if presence or absence of stressor control shapes HPA axis reactivity in a phobic fear exposure model. We recruited 19–45-year-old specific phobia participants (n=32 spider/snake phobia; n=14 claustrophobia) and gradually exposed them to their feared object or situation while measuring hormonal (ACTH and cortisol) and subjective (emotional distress, perceived control) responses. Utilizing a dyadic yoked design, we compared HPA reactivity when the pace of exposure was controlled by participants to identical exposure given to matched participants in the absence of control. Results showed that phobic fear exposure generated intense emotional distress without a corresponding increase in HPA axis activity. Although our actual manipulation of control failed to impact HPA responses, perceived control during exposure was associated with lower cortisol, an effect that was moderated by actual availability of stressor control. Our findings replicate Curtis‘ findings and challenge the still common but unsupported assumption that HPA axis activity reflects subjective distress. These results also highlight the importance of both perceived and actual aspects of stressor control in understanding what is truly “stressful” to the HPA axis system.

Investigating the effect of acute sleep deprivation on hypothalamic-pituitary-adrenal-axis response to a psychosocial stressor

The hypothalamic-pituitary-adrenal (HPA) axis has been previously identified as one potential mechanism that may explain the link between sleep deprivation and negative health outcomes. However, few studies have examined the direct association between sleep deprivation and HPA-axis functioning, particularly in the context of stress. Therefore, the aim of the current study was to investigate the relationship between acute sleep deprivation and HPA-axis reactivity to a psychosocial stressor. Participants included 40 healthy, young adults between the ages of 18–29. The current protocol included spending two nights in the laboratory. After an adaptation night (night 1), participants were randomized into either a sleep deprivation condition (29 consecutive hours awake) or a control condition (night 2). Following the second night, all participants completed the Trier Social Stress Test (TSST). Salivary cortisol was collected before, during, and after the TSST. Results indicated that there were significant group differences in cortisol stress reactivity. Specifically, compared to participants in the control condition, participants in the sleep deprivation condition had greater baseline (i.e., pre-stress) cortisol, yet a blunted cortisol response to the TSST. Taken together, a combination of elevated baseline cortisol (and its subsequent effect on HPA-axis regulatory processes) and a relative ‘ceiling’ on the amount of cortisol a laboratory stressor can produce may explain why participants in the sleep deprivation condition demonstrated blunted cortisol responses.

Change in urinary cortisol excretion mediates the effect of angry/hostile mood on 9 month diastolic blood pressure in HIV+ adults.

Cardiovascular disease is a growing concern in HIV disease management and nearly 1 out of 3 persons living with the virus is hypertensive. Biobehavioral factors such as anger, hostility, and HPA axis reactivity are emperically linked to blood pressure regulation. Whether HPA axis or mood disturbance increases risk for hypertension remains unclear in HIV disease. The aim of this study was to determine whether 9-month change in angry/hostile mood predicts alterations in systolic (SBP) or diastolic blood pressure (DBP), and whether this change is mediated by 24-h urinary cortisol (CORT)output. Sixty-one HIV positive adults, aged 41.1±8.6years, assigned to the control condition of a stress management intervention provided blood samples, 24-h urine specimens, blood pressurein-office, and self-reported mood at baseline and a 9-month follow-up. CORT was tested as a mediator in two separate models controlling for baseline BP, CD4 count, HIV-1 viral load, protease inhibitor use, body mass index, smoking status, and family history of cardiometabolic disease. Increase in angry/hostile mood was associated with greater SBP (β=0.33, CI 0.09, 0.56, p=0.01) and DBP (β=0.39, CI 0.16, 0.62, p<0.001) at follow-up. CORT partially mediated the effect of angry/hostile mood on DBP (β=0.28, CI 0.03, 0.54, p=0.03). Change in CORT was not related to SBP (β=0.12, CI -0.20, 0.44, p=0.46). The final mediation model accounted for 41.2% of the variance in 9-month DBP. Angry or hostile mood may contribute to increased risk for hypertension in persons treated for HIVvia disturbance of the HPA-axis.

Dimensions of Adversity, Physiological Reactivity, and Externalizing Psychopathology in Adolescence: Deprivation and Threat.

Dysregulation of autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis function is a putative intermediate phenotype linking childhood adversity (CA) with later psychopathology. However, associations of CAs with autonomic nervous system and HPA-axis function vary widely across studies. Here, we test a novel conceptual model discriminating between distinct forms of CA (deprivation and threat) and examine their independent associations with physiological reactivity and psychopathology. Adolescents (N = 169; mean [SD] age, 14.9 [1.4] years) with a range of interpersonal violence (e.g., maltreatment, community violence) and poverty exposure participated in the Trier Social Stress test (TSST). During the TSST, electrocardiogram, impedance cardiograph, salivary cortisol, and dehydroepiandrosterone-sulfate data were collected. We compared the associations of poverty (an indicator of deprivation) and interpersonal violence (an indicator of threat) on sympathetic, parasympathetic, and HPA-axis reactivity to the TSST, and assessed whether these differences mediated the association of adversity with internalizing and externalizing symptoms. Exposure to poverty and interpersonal violence was associated with psychopathology. Interpersonal violence, adjusting for poverty, was associated with blunted sympathetic (b = 1.44, p = .050) and HPA-axis reactivity (b = -.09; p = .021). Blunted cortisol reactivity mediated the association of interpersonal violence with externalizing, but not internalizing, psychopathology. In contrast, poverty was not associated with physiological reactivity after adjusting for interpersonal violence. We provide evidence for distinct neurobiological mechanisms through which adversity related to poverty and interpersonal violence is associated with psychopathology in adolescence. Distinguishing distinct pathways through which adversity influences mental health has implications for preventive interventions targeting youths exposed to childhood adversity.

Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication.

The stress response has been largely modified in all domesticated animals, offering a strong tool for genetic mapping. In chickens, ancestral Red Junglefowl react stronger both in terms of physiology and behavior to a brief restraint stress than domesticated White Leghorn, demonstrating modified functions of the hypothalamic–pituitary–adrenal (HPA) axis. We mapped quantitative trait loci (QTL) underlying variations in stress-induced hormone levels using 232 birds from the 12th generation of an advanced intercross between White Leghorn and Red Junglefowl, genotyped for 739 genetic markers. Plasma levels of corticosterone, dehydroepiandrosterone (DHEA), and pregnenolone (PREG) were measured using LC-MS/MS in all genotyped birds. Transcription levels of the candidate genes were measured in the adrenal glands or hypothalamus of 88 out of the 232 birds used for hormone assessment. Genes were targeted for expression analysis when they were located in a hormone QTL region and were differentially expressed in the pure breed birds. One genome-wide significant QTL on chromosome 5 and two suggestive QTL together explained 20% of the variance in corticosterone response. Two significant QTL for aldosterone on chromosome 2 and 5 (explaining 19% of the variance), and one QTL for DHEA on chromosome 4 (explaining 5% of the variance), were detected. Orthologous DNA regions to the significant corticosterone QTL have been previously associated with the physiological stress response in other species but, to our knowledge, the underlying gene(s) have not been identified. SERPINA10 had an expression QTL (eQTL) colocalized with the corticosterone QTL on chromosome 5 and PDE1C had an eQTL colocalized with the aldosterone QTL on chromosome 2. Furthermore, in both cases, the expression levels of the genes were correlated with the plasma levels of the hormones. Hence, both these genes are strong putative candidates for the domestication-induced modifications of the stress response in chickens. Improved understanding of the genes associated with HPA-axis reactivity can provide insights into the pathways and mechanisms causing stress-related pathologies.

Association of attachment disorganization, attachment-related emotion regulation, and cortisol response after standardized psychosocial stress procedure: A pilot study

Attachment representations are related to maintaining biological homeostasis, including physiological stress and emotional regulation. Therefore, recent research has focused on attachment stress regulation and hypothalamus pituitary adrenal (HPA) axis reactivity. However, the attachment disorganization underlying emotion regulation associated with the HPA axis response has not yet been investigated. In our study, the attachment representation and the HPA-axis reactivity by cortisol level before and after the Trier Social Stress Test were assessed in a sample of 98 healthy non-clinical subjects. As expected, approximately 30% of this sample showed a disorganized attachment representation. The subjects? unresolved attachment (breakdown of emotional regulation) showed a prolonged cortisol recovery. No differences were found between the attachment patterns in the increase and the delta of the cortisol response. However, the cortisol reactivity differed significantly for the occurrence of emotional regulation. The subjects with a high occurrence of attachment-related emotion regulation showed a higher cortisol response than the subjects with an unresolved attachment and the ones with a low occurrence of attachment-related emotion regulation. Regulating the negative emotions of stressful situations may require more attention as it might lead to an increased activation of the physiological system.

Trait and state rumination interact to prolong cortisol activation to psychosocial stress in females

There is a growing realization that cognitive processes associated with stress coping, such as rumination and distraction, can impact the hypothalamic-pituitary-adrenal-axis (HPA-axis). Yet, little is known about what aspects of the HPA-axis stress response (rate of activation, duration of activation, rate of recovery) is impacted by such cognitive processes. This study examines the impact of both ruminative trait tendencies and experimentally induced rumination on salivary cortisol responses to a social evaluative stress task. Participants (n=71) were exposed to the Trier Social Stress Test (TSST) and were then randomized to complete either a rumination or distraction task. Trait rumination was also assessed at baseline. Results showed no main effects of either trait rumination or experimental condition, but they interacted to predict the cortisol response. Specifically, participants high in trait rumination had prolonged duration of cortisol activation in the rumination condition, compared to those in the distraction condition. In contrast, cortisol responses of participants with low trait rumination did not differ by condition. Notably, our interaction effect was only significant in females. Our findings highlight the complex relationship between rumination and HPA-axis activity, suggesting an interaction of trait and state rumination in shaping HPA-axis responses to stress, and call attention to sex differences in this relationship.

Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats

Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that metabolic risk markers arise when vulnerable individuals are exposed to social challenges later in life.

HPA-axis activation as a key moderator of childhood trauma exposure and adolescent mental health

Individual differences in a child’s sensitivity to stress may influence whether youth exposed to trauma develop symptoms of psychopathology. We examined the interaction between HPA-axis reactivity to an acute stressor and exposure to different types of childhood trauma as predictors of mental health symptoms in a sample of youth. Youth (n = 121, ages 9–16; 47% female) completed a standardized stress task, including 5 post-stress salivary cortisol samples. Parents also completed the Child Behavior Checklist as a measure of child internalizing and externalizing symptoms in the past month, and completed the Early Trauma Inventory (ETI) as a measure of their child’s trauma exposure. More emotional abuse and non-intentional trauma were associated with greater internalizing symptoms. Youth exposed to physical abuse who demonstrated slower HPA-axis reactivity had elevated internalizing and externalizing symptoms. Youth exposed to emotional abuse or non-intentional traumatic events who demonstrated faster HPA-axis reactivity had elevated internalizing and externalizing symptoms. Profiles of exaggerated or attenuated HPA-axis reactivity to acute stress may be risk factors for psychopathology in children facing different stressful social environments.

Changes in HPA-axis reactivity by subjective well-being: Impact of loneliness, gender and serotonin transporter genotype

Changes in HPA-axis reactivity by subjective well-being: Impact of loneliness, gender and serotonin transporter genotype

Impact of DHEA to cortisol ratios on HPA-axis reactivity: Moderation by sex and age

Impact of DHEA to cortisol ratios on HPA-axis reactivity: Moderation by sex and age

Acute cortisol reactivity attenuates engagement of fronto-parietal and striatal regions during emotion processing in negative mood disorders

ObjectiveDepression and bipolar disorder (negative mood disorders, NMD) are associated with dysregulated hypothalamic-pituitary-adrenal (HPA)-axis function and disrupted emotion processing. The neural networks involved in attenuation of HPA-axis reactivity overlap with the circuitry involved in perception and modulation of emotion; however, direct links between these systems are understudied. This study investigated whether cortisol activity prior to undergoing fMRI was related to neural processing of emotional information in participants with NMD. MethodsForty-one adults (Mage=40.33, SD=15.57) with major depression (n=29) or bipolar disorder (n=12) and 23 healthy control comparisons (Mage=36.43, SD=17.33) provided salivary cortisol samples prior to completing a facial emotion perception test during 3-Tesla fMRI. ResultsOverall, pre-scan cortisol level was positively associated with greater engagement of the dorsal anterior cingulate (dACC), inferior parietal lobule, insula, putamen, precuneus, middle and medial frontal and postcentral gyri, posterior cingulate, and inferior temporal gyrus during emotion processing of all faces. NMD status moderated this effect; in NMD participants’ pre-scan cortisol was associated with attenuated activation of the insula, postcentral gyrus, precuneus, and putamen for fearful faces and the medial frontal gyrus for angry faces relative to HCs. Cortisol-related attenuation of activation among NMD participants was also observed for facial identification in the dACC, putamen, middle temporal gyrus, precuneus, and caudate. ConclusionsAcross all participants, cortisol was associated with greater activation in several regions involved in the perception and control of emotion. However, cortisol responsivity was associated with hypoactivation of several of these regions in the NMD group, suggesting that HPA-axis activity may selectively interfere with the potentially adaptive recruitment of circuits supporting emotion perception, processing and/or regulation in mood disorders.

Antidepressant treatment differentially affects the phenotype of high and low stress reactive mice

Modelling key endophenotypes can be a powerful approach to gain insight into mechanisms underlying the aetiology and pathophysiology of neuropsychiatric disorders. Based on evidence of stress hormone system dysregulations in depression, the Stress Reactivity (SR) mouse model has been generated by a selective breeding approach for extremes in HPA axis reactivity, resulting in high (HR), intermediate (IR) and low (LR) reactive mice. The characterisation of their phenotypic alterations has highlighted many similarities of HR and LR mice with the melancholic and atypical depression, respectively. We therefore aimed to examine whether the antidepressant fluoxetine (10 mg/kg/day i.p., 4–5 weeks) can ameliorate the phenotypic characteristics of HR and LR mice in neuroendocrine functions (HPA axis basal activity, stress reactivity, negative feedback), emotional reactivity/coping-strategy (open field, forced swim tests), spatial learning/memory (Morris water-maze) and hippocampal neurogenesis. Line differences in HPA axis reactivity were maintained under fluoxetine treatment. However, we observed fluoxetine effects on glucocorticoid-induced negative feedback, stress-coping behaviours, cognitive functions and neurogenesis. Specifically, our results revealed line-dependent consequences of fluoxetine treatment: (1) an amelioration of the ‘melancholic-like’ features of HR mice (reversing the negative feedback resistance, the hyperactive coping style and the memory deficits; increasing hippocampal neurogenesis); (2) an exacerbation of the phenotypic deviations of LR mice (increasing their pronounced negative feedback and passive coping style). Thus, these findings support the predictive validity of antidepressant treatment in the HR mouse line and emphasize the translational value of the SR mouse model for the development of therapeutic strategies based on endophenotype-driven classifications.

Predisposition or side effect of the duration: the reactivity of the HPA-axis under psychosocial stress in panic disorder

BackgroundPanic disorder (PD) has been associated with an altered reactivity of the hypothalamic–pituitary–adrenocortical (HPA) system under psychosocial stress. Until now it remains unclear whether a diminished cortisol release is an early risk factor predisposing for PD or a consequence of PD. In order to unravel this point, the present study compares the cortisol secretion between patients with a recent onset and a chronic course of PD. MethodsThe Trier Social Stress Test (TSST) was applied in patients with a duration of PD≤1.5years (N=35), patients with a duration of PD>1.5years (N=56) and healthy controls (N=95). Salivary cortisol and heart rate (HR) were assessed as primary outcomes. ResultsAccording to baseline cortisol/baseline HR and HR response there was no significant difference. Both patient groups (≤1.5/>1.5years) showed a blunted cortisol response with no significant group difference. In multiple linear regression models the attenuation of the HPA-axis was largely accounted for by group, smoking status, use of contraceptive pill and the interaction group by gender. Female patients with a chronic course showed the lowest cortisol response under the TSST. ConclusionsIt might be assumed that a decreased reactivity of the HPA-axis could be considered as etiological risk factor in the preliminary stages of PD. Above, female gender, smoking status and the use of contraceptive pill seem to further moderate the attenuated HPA-axis response pattern in patients with PD.

Fluoxetine normalizes the effects of prenatal maternal stress on depression- and anxiety-like behaviors in mouse dams and male offspring

Maternal depression during pregnancy and the postpartum period (lactation) is a common debilitating condition affecting mother-fetus/-infant interactions, which can be a risk factor for cognitive and affective disorders in mothers and their children. Selective-serotonin-reuptake-inhibitor-(SSRI) pharmacotherapy is known as the first-line treatment of maternal depression. However, its use during pregnancy and lactation is a topic of concern. The present study aimed to investigate the effects of prenatal stress alone or in combination with fluoxetine (FLX) on hypothalamic–pituitary–adrenal axis (HPA) activity, anxiety-/depression-like behaviors in dams and in offspring. To do this, gestationally-stressed and non-stressed mouse dams were orally treated with FLX-(8/mg/kg/day) from gestational day 10 to lactation day 20. The behavioral outcomes of prenatal stress and FLX treatment in dams and male offspring were assessed using the sucrose preference, forced swim, zero maze, and light-dark box tests. Stress-induced corticosterone levels were also evaluated as indicative of abnormal HPA-axis function. Our findings indicated that maternal stress resulted in increased depression-like behavior and HPA axis hyperactivity in dams during pregnancy and lactation which were reversed by FLX. Furthermore, prenatal stress increased anxiety/depression-like behaviors and HPA-axis reactivity in male offspring. These effects were reversed by maternal FLX treatment. Developmental FLX exposure, without prenatal stress, did not have any adverse effects on the above measured parameters. Our results suggest that prenatal stress induces maternal depression-like behavior which affects the development of affective symptoms in male offspring, and that remediation of maternal depression-like behavior coincidences with the normalization of anxiety-and depression-like symptoms in male offspring.