Psychosocial Stress In Humans Research Articles

Social high performers under stress behave more prosocially and detect happy emotions better in a male sample

Psychosocial stress is increasing in society, impacting our lives in all social domains. However, the conditions under which stress facilitates (“tend-and-befriend”) or hinders (“fight-or-flight”) social approach remain elusive. We tested whether previous heterogeneous findings might be resolved by accounting for individual differences in social performance under stress. For that purpose, we introduce the novel Trier Social Stress Test (TSST) social performance index that was aggregated across ratings from two independent observers. Moreover, we apply an innovative setup enabling electroencephalographic (EEG) data to be measured inside an electrically-shielded cabin during stress, namely the TSST-EEG. Relying on a sample of 59 healthy male participants, we collected behavioral (i.e., sharing resources with others) and cognitive (i.e., detecting facial emotional expressions) approach patterns while participants experienced either acute psychosocial stress (n = 31) or no stress (control condition; n = 28) and while EEG was being recorded. During stress exposure, high-performing participants behaved more prosocially, and differentiated better between happy and neutral emotions on both behavioral and neurophysiological levels (revealed by intensity differences in a N170-like response). Overall, our findings demonstrate the added value of both the novel TSST social performance index and the novel TSST-EEG setup. By showing that high social performance during the TSST is associated with behavioral, cognitive, and neurophysiological approach patterns, our study offers valuable insights into adaptive or maladaptive psychobiological mechanisms in coping with psychosocial stress. Future stress research should address the role of social performance differences during stress in social interaction to better understand the behavioral consequences of psychosocial stress in humans.

Dissociation of endocrine responses to the Trier Social Stress Test in Virtual Reality (VR-TSST) by the benzodiazepine alprazolam and the translocator protein 18 kDa (TSPO) ligand etifoxine

BackgroundActivity of the two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis, has already been shown to be modulated by different compounds that bind to the central benzodiazepine receptor. Less is known about ligands that modulate the peripheral benzodiazepine receptor – meanwhile known as the translocator protein 18 kDa (TSPO) – which constitute promising candidates in the search of novel anxiolytics. To close this gap, the present study compared the effects of the benzodiazepine alprazolam and the TSPO ligand etifoxine on responses of the HPA and SAM axes to the Trier Social Stress Test, a standardized paradigm to induce acute psychosocial stress in humans, performed in Virtual Reality (VR-TSST). MethodsSixty healthy males, aged between 18 and 55 years, were randomly assigned to receive either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine, or placebo over five days. On the last day of intake, they were exposed to the VR-TSST. We assessed changes of salivary cortisol, allopregnanolone, (nor-) epinephrine in serum, TSPO expression in platelets as well as heart rate (HR), skin conductance level (SCL) and self-reports in response to the stress task. Repeated measures ANOVAs were conducted to examine treatment effects on these stress response variables during the course of VR-TSST. ResultsThe response of salivary cortisol to the VR-TSST was significantly blunted in participants pre-treated with alprazolam but was not affected by etifoxine. While levels of allopregnanolone, epinephrine and norepinephrine increased in response to stress, TSPO expression decreased. None of those endocrine stress markers was affected by the active treatments, whereas TSPO expression increased after etifoxine administration over all study days. There were no effects of the two anxiolytics on HR, SCL or any self-report measurement. ConclusionThe current study confirmed the attenuating effects of benzodiazepines on stress-induced HPA axis activity but did not reveal a comparable effect of the TSPO ligand etifoxine. The long-term consequences of a pharmacologically blunted response of the HPA axis to an acute stressor should be further elucidated. Due to the missing effects of etifoxine on stress-related parameters in our sample of healthy subjects, it might be concluded that the therapeutic effects of this TSPO ligand are restricted to stronger or pathological stress responses, respectively.

Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans

Both preclinical and clinical evidence suggests that the endogenous opioid system is involved in responses to stress. For example, in animal models opioid agonists reduce isolation distress whereas opioid antagonists increase isolation distress. We recently reported that the mixed mu agonist and kappa antagonist buprenorphine dampened responses to acute psychosocial stress in humans. Now we extend this to study the effects of a pure mu-opioid agonist, hydromorphone, and a non-opioid analgesic, acetaminophen, on response to social stress. We compared the effect of hydromorphone (2 and 4 mg), acetaminophen (1000 mg) to a placebo using a between subject design. Healthy adult volunteers were randomly assigned to receive placebo (N = 13), 2 mg hydromorphone (N = 12), 4 mg hydromorphone (N = 12), or 1000 mg acetaminophen (paracetamol; N = 13) under double-blind conditions before undergoing a stress task or a control task on two separate sessions. The stress task, consisting of a standardized speaking task and the non-stressful control task were presented in counterbalanced order. Dependent measures included mood ratings, subjective appraisal of the stress (or no-stress) task, salivary cortisol, pupil diameter, heart rate, and blood pressure. The stress task produced its expected increase in heart rate, blood pressure, salivary cortisol, pupil diameter, and subjective ratings of anxiety and negative mood. Hydromorphone dose-dependently dampened cortisol responses to stress, and decreased ratings of how “challenging” participants found the task. Acetaminophen did not affect physiological responses, but, like hydromorphone, decreased ratings of how “challenging” the task was. The hydromorphone results support the idea that the mu-opioid system is involved in physiological responses to acute stress in humans, in line with results from preclinical studies. The non-opioid analgesic acetaminophen did not dampen physiological responses, but did reduce some components of psychological stress. It remains to be determined how both opioid and non-opioid systems mediate the complex physiological and psychological responses to social stress.

Psychosocial Stress and Immunity-What Can We Learn From Pig Studies?

Psychosocial stress may impair immune functions and provoke the development of pathologies. The underlying communication between the brain and the immune system is being studied predominantly in rodents. However, pigs offer several advantages as preclinical models for humans because pigs are more similar to humans than rodents in many anatomical and physiological characteristics. Unlike in rodents, the main stress-induced glucocorticoid in humans and pigs is cortisol with a similar circadian rhythm. In this study, we summarize data on short-term and long-term effects of social stress in pigs for their immunity and neuroendocrine regulation with consequences for their health and well-being. As typical social stressors, regrouping, crowding, social isolation, and maternal deprivation have been studied. Psychosocial stress in pigs may affect various reactions of innate and adaptive immunity, such as leukocyte distribution, cytokine secretion, lymphocyte proliferation, and antibody production as well as immune responses to viral infection or vaccination. Furthermore, social stress may induce or promote gastrointestinal diseases through dysregulation of inflammatory processes. In piglets, psychosocial stress may also result in glucocorticoid resistance of lymphocytes, which has been discussed as a cause of allergic asthma in humans. Stress-related neuroendocrine alterations in the cortico-limbic structures, such as the prefrontal cortex, amygdala, hippocampus and hypothalamus, have been demonstrated in pigs at different ages. Based on these data, we propose using pigs as models for psychosocial stress in humans to study the mechanisms of brain-to-immune and immune-to-brain communication from the systemic level down to the cellular and subcellular levels.

The plasma interleukin-6 response to acute psychosocial stress in humans is detected by a magnetic multiplex assay: comparison to high-sensitivity ELISA

Circulating concentrations of interleukin (IL)-6, an inflammatory biomarker widely assessed in humans to study the inflammatory response to acute psychological stress, have for decades been quantified using enzyme-linked immunosorbent assay (ELISA). However, biobehavioral researchers are increasingly using cytokine multiplex assays instead of ELISA to measure IL-6 and other cytokines. Despite this trend, multiplex assays have not been directly compared to ELISA for their ability to detect subtle stress-induced changes of IL-6. Here, we tested the prediction that a high-sensitivity multiplex assay (human Magnetic Luminex Performance Assay, R&D Systems, Minneapolis, MN) would detect changes in IL-6 as a result of acute stress challenge in a manner comparable to high-sensitivity ELISA. Blood was collected from 12 healthy adults immediately before and then 90 and 210 min after the start of the Trier Social Stress Test (TSST), an acute laboratory psychosocial stress challenge. In addition to quantifying IL-6 concentrations in plasma with both multiplex and ELISA, we also assessed concentrations of tumor necrosis factor-alpha, IL-8, IL-10, IL-5, and IL-2 with multiplex. The multiplex detected IL-6 in all samples. Concentrations strongly correlated with values determined by ELISA across all samples (r = 0.941, p < .001) as well as among samples collected at individual TSST time points. IL-6 responses to the TSST (i.e. area under the curve) captured by multiplex and ELISA were also strongly correlated (rs = 0.937, p < .001). While other cytokines were detected by multiplex, none changed as a result of TSST challenge at time points examined. These results suggest high-sensitivity magnetic multiplex assay is able to detect changes in plasma concentrations of IL-6 as a result of acute stress in humans.

Extramedullary monopoiesis underlies stress-sensitization and recurring anxiety

In humans, chronic stress is associated with an increased prevalence of mental health complications including anxiety and depression. Repeated social defeat (RSD) in mice recapitulates key deficits associated with psychosocial stress in humans. We showed that exposure to sub threshold stress 24 days after RSD caused the recurrence of anxiety that was dependent on monocyte trafficking from the spleen to the brain. We hypothesized that extramedullary production of monocytes in the spleen underlies enhanced monocyte trafficking and recurring anxiety following psychosocial stress. Here, RSD substantially increased the presence of proliferating hematopoietic stem progenitor cells (HSPCs) within the splenic red pulp. BrdU pulse chase experiments confirmed that RSD increased the presence of proliferated monocytes in the spleen. Next, extramedullary hematopoiesis and monocyte proliferation in the spleen was assessed 24 days after RSD. Increased presence of HSPCs was still maintained in the spleen 24 days after RSD. Similarly, BrdU pulse chase 24 days later revealed that the spleen maintained monocyte proliferation over this period. These data indicate that RSD caused extramedullary hematopoiesis that resulted in long term monocyte proliferation in the spleen that persisted for at least 24 days that contributed to enhanced monocyte trafficking and stress-sensitization.

Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans

Pre-clinical and clinical evidence indicates that opioid drugs have stress-dampening effects. In animal models, opioid analgesics attenuate responses to isolation distress, and in humans, opioids reduce stress related to anticipation of physical pain. The stress-reducing effects of opioid drugs may contribute to their abuse potential. Despite this evidence in laboratory animals, the effects of opioids on responses to psychosocial stress have not been determined in humans. Here we examined the effects of buprenorphine, a μ-opioid partial agonist used to treat opioid dependence and pain, on subjective and physiological responses to a stressful public speaking task in healthy adults. We hypothesized that buprenorphine would reduce subjective and physiological stress responses. Healthy adult volunteers (N=48) were randomly assigned to receive placebo, 0.2mg sublingual buprenorphine, or 0.4mg sublingual buprenorphine in a two-session study with a stressful speaking task (Trier Social Stress Test; TSST) and a non-stressful control task. During the sessions, the participants reported on their mood states, provided subjective appraisals of the task, and measures of salivary cortisol, heart rate, and blood pressure at regular intervals. Stress produced its expected effects, increasing heart rate, blood pressure, salivary cortisol, and subjective ratings of anxiety and negative mood. In line with our hypothesis, both doses of buprenorphine significantly dampened salivary cortisol responses to stress. On self-report ratings, buprenorphine reduced how threatening participants found the tasks. These results suggest that enhanced opioid signaling dampens responses to social stress in humans, as it does in laboratory animals. This stress-dampening effect of buprenorphine may contribute to the non-medical use of opioid drugs.

70. Sympathetic innervation initiates myeloid cell trafficking from the spleen to the brain that causes the re-establishment of anxiety in stress-sensitized mice

Repeated social defeat (RSD) in mice recapitulates key immunological, physiological, and behavioral deficits associated with psychosocial stress in humans. We have reported that exposure to sub-threshold stress 24 days after RSD caused re-establishment of anxiety that was dependent on myeloid cell trafficking from the spleen to the brain. Therefore, we hypothesized that the spleen of RSD-exposed mice becomes a critical reservoir of reactive myeloid cells that are rapidly released following sympathetic activation by sub-threshold stressors. In the first experiments, the spleen was removed before 6 cycles of RSD yet this did not alter initial stress-induced myeloid redistribution or anxiety. Splenectomy prior to RSD, however, prevented the re-distribution of myeloid cells and re-establishment of anxiety following sub-threshold stress 24 days after RSD. Thus, the spleen did not contribute to myeloid cell trafficking and anxiety immediately following RSD, but rather served as a reservoir of myeloid cells that are readily released following sub-threshold stress. To address how these cells are released from the spleen, control and RSD-sensitized mice were treated with guanethidine, a peripheral sympathetic inhibitor, 24 days after RSD prior to sub-threshold stress. Intervention with guanethidine, prior to sub-threshold stress blocked myeloid cell redistribution and anxiety in RSD-sensitized mice. Thus, sympathetic initiation of spleen-to-brain myeloid cell trafficking represents a novel mechanism in the context of recurring anxiety disorders.

Dopamine response to psychosocial stress in humans and its relationship to individual differences in personality traits

BackgroundPrevious studies have reported inter-individual variability in the dopamine (DA) response to stress. This variability might be related to individual differences in the vulnerability to experience the negative effect of stress. ObjectiveTo investigate whether personality traits as measured by the Revised NEO Personality Inventory explain variability in DA response to a psychosocial stress task. MethodsEleven healthy adults, mean age of 26 ± 3.87 underwent two Positron Emission Tomography (PET) scans using the dopamine D2/3 agonist, [11C]-(+)-PHNO under a control and stress condition. The Simplified Reference Tissue Model (SRTM) was used to obtain [11C]-(+)-PHNO Binding Potential (BPND). Stress-induced DA response was indexed as a percent change in [11C]-(+)-PHNO BPND between control and stress conditions. The regions of interest were defined into D2-rich regions, which included the Associative and Sensorimotor Striatum (AST and SMST); D2/3 mixed regions, which included the Limbic Striatum (LST) and Globus Pallidus (GP); and D3-rich region, which included the Substantia Nigra (SN). ResultsSeveral personality traits within the Neuroticism and Openness to Experience domain were significantly correlated with blunted DA response to stress. Specifically, the Angry-Hostility, Vulnerability, and Depression trait were associated with blunted DA stress response in the AST (r = −0.645, p = 0.032), LST (r = −0.677, p = 0.022) and GP (r = −0.736, p = 0.010), respectively. The Openness to Values was correlated with a decreased DA release in the SN (r = −0.706, p = 0.015). ConclusionVariability in DA stress response might be related to individual differences in personality.

Social subordination produces distinct stress-related phenotypes in female rhesus monkeys

Social subordination in female macaques is imposed by harassment and the threat of aggression and produces reduced control over one's social and physical environment and a dysregulation of the limbic-hypothalamic-pituitary-adrenal axis resembling that observed in people suffering from psychopathologies. These effects support the contention that this particular animal model is an ethologically relevant paradigm in which to investigate the etiology of stress-induced psychological illness related to women. Here, we sought to expand this model by performing a discriminate analysis (DA) on 33 variables within three domains; behavioral, metabolic/anthropomorphic, and neuroendocrine, collected from socially housed female rhesus monkeys in order to assess whether exposure to social subordination produces a distinct phenotype. A receiver operating characteristic (ROC) curve was also calculated to determine each domain's classification accuracy. DA found significant markers within each domain that differentiated dominant and subordinate females. Subordinate females received more aggression, showed more submissive behavior, and received less of affiliation from others than did dominant females. Metabolic differences included increased leptin, and reduced adiponectin in dominant compared to subordinate females. Dominant females exhibited increased sensitivity to hormonal stimulation with higher serum LH in response to estradiol, cortisol in response to ACTH, and increased glucocorticoid negative feedback. Serum oxytocin, CSF DOPAC and serum PACAP were all significantly higher in dominant females. ROC curve analysis accurately predicted social status in all three domains. Results suggest that socially house rhesus monkeys represent a cogent animal model in which to study the physiology and behavioral consequences of chronic psychosocial stress in humans.

Rise in Plasma Lactate Concentrations with Psychosocial Stress: A Possible Sign of Cerebral Energy Demand

Objective: It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. Methods: 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. Results: Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R² = 0.221, p = 0.02) and ACTH concentrations (R² = 0.460, p < 0.001). Conclusion: Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as ‘cerebral lactate demand’.

Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [18F]fallypride

Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D₂/₃ PET radioligand [¹⁸F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹⁸F]fallypride displacement. Voxel-based statistical maps, representing specific D₂/₃ binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

Investigations on light induced stress model and on the role of Phyllanthus amarus in attenuation of stress related depression with focus on 5HT2Am- RNA expression.

There is an increasing evidence that psychological stress and depression trigger changes in various biochemical parameters in animals and human subjects. Chronic stress in rats, and psychosocial stress in humans, is implicated in the pathophysiology of mood and anxiety disorders. The current study was been designed to investigate the behavioral, anatomical status of rat brain and expression of serotonin receptor (5HT2A) mRNA related to pathophysiology of stress after high light (HL) illumination and to evaluate the effect of Phyllanthus amarus (PA) over such stress induced changes in mid brain and prefrontal cortex region of rat brain. Bright light illumination was used to induce stress in wistar rats. Established methods were used to analyse biochemical and histopathological tests. PA administration to HL stressed animals for 7 days prevented stress-induced oxidative damage, as evidenced by significant enhancement of key endogenous antioxidant defense components. HL stress also caused reduced activities of membrane bound enzymes in synaptic membrane along with reduced levels of lipid profile and glycoprotein in the midbrain region. Stress induced changes in the locomotor activity, time spent for exploring the center of the arena, frequency of rearing and grooming, and frequency of facing the corner of the arena, were altered on PA administration. The findings suggest that the therapeutic efficacy of PA may be mediated, atleast partially, via reversal of oxidative damage. Further the study demonstrates the promising intervention by PA on the mRNA expression of 5HT 2A in the brain. These preliminary results pave the way for further validation of PA against stress.

Effects of acute psychosocial stress on working memory related brain activity in men

Acute psychosocial stress in humans triggers the release of glucocorticoids (GCs) and influences performance in declarative and working memory (WM) tasks. These memory systems rely on the hippocampus and prefrontal cortex (PFC), where GC-binding receptors are present. Previous studies revealed contradictory results regarding effects of acute stress on WM-related brain activity. We combined functional magnetic resonance imaging with a standardized psychosocial stress protocol to investigate the effects of acute mental stress on brain activity during encoding, maintenance, and retrieval of WM. Participants (41 healthy young men) underwent either a stress or a control procedure before performing a WM task. Stress increased salivary cortisol levels and tended to increase WM accuracy. Neurally, stress-induced increases in cortical activity were evident in PFC and posterior parietal cortex (PPC) during WM maintenance. Furthermore, hippocampal activity was modulated by stress during encoding and retrieval with increases in the right anterior hippocampus during WM encoding and decreases in the left posterior hippocampus during retrieval. Our study demonstrates that stress increases activity in PFC and PPC specifically during maintenance of items in WM, whereas effects on hippocampal activity are restricted to encoding and retrieval. The finding that psychosocial stress can increase and decrease activity in two different hippocampal areas may be relevant for understanding the often-reported phase-dependent opposing behavioral effects of stress on long-term memory.

A Hypothesized Role for Dendritic Remodeling in the Etiology of Mood and Anxiety Disorders

A Hypothesized Role for Dendritic Remodeling in the Etiology of Mood and Anxiety Disorders

Hippocampal damage abolishes the cortisol response to psychosocial stress in humans

The hippocampus (HC) is necessary for learning and memory, but it also plays a role in other behaviors such as those related to stress and anxiety. In support of the latter idea, we show here that bilateral HC damage abolishes the cortisol response to psychosocial stress. We collected salivary cortisol, heart rate, and affective responses to the Trier Social Stress Test (TSST) from 7 participants with bilateral HC lesions, 12 participants with damage outside the HC, and 28 healthy normal comparison participants matched to the HC participants on age and sex. HC participants showed elevated pre-stress cortisol, but no cortisol response to the TSST. Heart rate and affective responses in the HC group were similar to those of the comparison groups. Participants with brain damage outside the HC showed stress responses that were comparable to those of the healthy comparison group. These findings support the idea that the functions of the human HC extend beyond learning and memory, and suggest that the HC is necessary for producing the cortisol response to psychosocial stress.

Determinants of the NF-κB response to acute psychosocial stress in humans

Previous research has shown that psychosocial stress is associated with an increased activity of the transcription factor nuclear factor-kappaB (NF-κB), a major inducer of inflammatory genes. While considerable individual variation has been noted, factors contributing to this variation have not been described so far.Therefore, 29 healthy participants (35.8±12yrs) were exposed to the Trier Social Stress Test. Blood was collected before and repeatedly afterward for determination of NF-κB activity, leukocyte subset numbers, cortisol, norepinephrine, and in vitro-stimulated IL-6 production. Additionally, age, sex, and ratings of perceived chronic and acute stress were assessed.Regression analyses revealed that older participants showed a lower NF-κB stress response compared to younger adults (β=−.42, p=.026). Higher NF-κB stress responses were associated with lower cortisol stress responses (β=−.37, p=.05), higher pre-stress IL-6 production (β=.38, p=.043), and high chronic in combination with low acute stress, or vice versa (β=−.61, p=.06). Norepinephrine and sex were not associated with NF-κB stress responses (all p⩾.13).In summary, the present study shows for the first time in human psychosocial stress the negative association of cortisol and NF-κB. This parallels results from in vitro studies. Our finding of lower NF-κB stress responses in older age and in people with high chronic and acute stress might be interpreted as an adaptive dampening of NF-κB activity. In the absence of longitudinal data, however, this interpretation remains speculative.

Chronic mild stress impairs cognition in mice: From brain homeostasis to behavior

Exposure to chronic stress in rodents and psychosocial stress in humans has been shown to alter cognitive functions and has been linked to the pathophysiology of mood disorders. The purpose of the present study was to investigate effects and possible mechanisms of a chronic mild stress (CMS) procedure on cognitive behaviors in Swiss albino mice using the object recognition test (ORT) and object location test (OLT). Results showed that CMS exposure impaired cognitive performance and produced amnesia of acquired information in both ORT and OLT. Furthermore, the cognitive impairment was coexistent with increased plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as with enhanced plasma levels of corticosterone (CORT), corticotrophin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH). In addition, severe neuronal cell damage was found, as bromodeoxyuridine (BrdU) positive cells and the expression of brain derived neurotrophic factor (BDNF) in dentate gyrus (DG) of hippocampus were decreased after 5 weeks CMS procedure. Taken together, these findings indicated that CMS exposure-induced impairment of cognitive behaviors might be attributed to the stress-related alterations in brain homeostasis that were reflected in changes in the neuroimmune and neuroendocrine systems as well as in neurogenesis.

Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats

Stress plays a potential role in the onset and exacerbation of depression. Chronic restraint stress in rats, and psychosocial stress in humans, is implicated in the pathophysiology of mood and anxiety disorders. Oxidative damage is an established outcome of restraint stress, which has been suggested to induce many damaging processes contributing to the pathology of stress-induced depression. However, the modulatory role of clinically effective antidepressants, such as fluoxetine, in attenuating oxidative stress has not been well characterized. Therefore, the current study was designed to investigate the antioxidant effects of chronic treatment with fluoxetine in animals submitted to restraint stress. The antioxidant potential of the antidepressant fluoxetine was compared with that of turmeric, used as a standard since it integrates both antioxidant and antidepressant properties. Chronic fluoxetine administration to stressed animals for 21 days prevented restraint stress-induced oxidative damage with an efficacy similar to that of turmeric, as evidenced by significant enhancement of key endogenous antioxidant defense components, comprising the free-radical scavenging enzymes, superoxide:superoxide oxidoreductase (EC 1.15.1.1), hydrogen-peroxide:hydrogen-peroxide oxidoreductase (EC 1.11.1.6), glutathione S-transferase (EC 2.5.1.18) and glutathione:NADP(+)oxidoreductase (EC 1.8.1.7), as well as non-enzymatic antioxidants, GSH, glucose and uric acid, which were severely depleted by restraint stress in animals receiving no treatment. Oxidative stress markers, (S)-lactate:NAD(+) oxidoreductase activity (EC 1.1.1.27), malondialdehyde levels (lipid peroxidation product) and protein carbonyl content were also significantly decreased following fluoxetine treatment. Both these drugs when given alone to non-stressed animals did not alter basal levels of antioxidant defense components and oxidative stress markers significantly. Our findings suggest that the therapeutic efficacy of fluoxetine may be mediated, at least partially, via reversal of oxidative damage as demonstrated by protective enhancement of antioxidant status following a stress-induced decline. In addition, this study demonstrates important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in stress-induced depression.

Preventive action of Ginkgo biloba in stress- and corticosterone-induced impairment of spatial memory in rats

In this study, we tested preventive effects of a natural medicine the extract of Ginkgo biloba (EGB 761) on post-stress cognitive dysfunction. Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and have been linked to the pathophysiology of mood and anxiety disorders. Our findings indicate that chronic restraint stress impaired egocentric spatial memory as observed in the eight-arm radial maze but it did not alter the allocentric spatial memory in the Morris water maze. In control rats EGB 761 (100mg/kg, orally) improved spatial memory in these two tests. Also, EGB 761 normalized cognitive deficits seen in rats chronically stressed or treated with an 'equivalent' dose of exogenous corticosterone (5mg/kg, subcutaneously). We conclude that, in rats, repeated administration of EGB 761 prevents stress- and corticosterone-induced impairments of spatial memory.