Gingko biloba extract diminishes stress-induced memory deficits in rats

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 has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and undesired effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2 h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg/kg) impaired nonspatial memory as measured by an object recognition test. In control rats, EGB 761 improved spatial and nonspatial memory in Morris water maze and object recognition tests. Preventive doses of EGB 761 (100 mg/kg) normalized cognitive deficits, seen in rats chronically stressed or treated with corticosterone in object recognition test, and improved memory processes in these rats measured by Morris water maze test. There was no influence of our treatments on locomotor exploratory activity and anxiety measured in open field and elevated 'plus' maze tests, making a contribution of unspecific motor and emotional effects of the used drugs to their performance in the memory tests improbable.     

Two Chronic Stress Models Based on Movement Restriction in Rats Respond Selectively to Antidepressant Drugs: Aldolase C As a Potential Biomarker

Background:

Clinically depressed individuals respond to different types of antidepressants, suggesting that different neurobiological mechanisms may be responsible for their depression. However, animal models to characterize this are not yet available.

Methods:

We induced depressive-like behaviors in rats using 2 different chronic stress models: restraint in small cages or immobilization in adaptable plastic cones. Both models increased anxiety responses evaluated by novelty-suppressed feeding and the elevated plus-maze; increased learned helplessness evaluated by the tail suspension and forced swimming tests; and increased anhedonia evaluated by the sucrose preference test.

Results:

We assessed the ability of 2 different types of antidepressants to ameliorate depressive-like behaviors. We administered the serotonin reuptake inhibitor fluoxetine or the noradrenaline reuptake inhibitor reboxetine once daily for 28 days to rats that received either chronic restraint or immobilization stress, or no stress. Behavioral analysis revealed that fluoxetine ameliorated depressive-like behaviors when induced by chronic restraint stress, whereas reboxetine ameliorated these behaviors when induced by chronic immobilization stress. To further test biological differences between both models, we evaluated the levels of Aldolase C, an enzyme expressed by forebrain astrocytes that is regulated by antidepressant treatment, in the cerebrospinal fluid: chronic restraint stress, but not immobilization stress, increased the levels of Aldolase C. Moreover, the presence of astrocyte-derived Aldolase C-GFP in the cerebrospinal fluid indicates its central origin.

Conclusions:

Two stress paradigms induced depressive-like behaviors that were sensitive to different antidepressant treatments. Biomarkers such as Aldolase C could help determine optimal antidepressant treatments for clinically depressed patients.     

Prior multiple ethanol withdrawals enhance stress-induced anxiety-like behavior: inhibition by CRF1- and benzodiazepine-receptor antagonists and a 5-HT1a-receptor agonist.

Repeated withdrawals from chronic ethanol induce a persistent adaptive change. Further, stress substitutes for the initial two withdrawals of a multiple-withdrawal protocol to sensitize rats to withdrawal-induced anxiety-like behavior ('anxiety'). Therefore, it was tested whether the persistent adaptation induced by multiple-withdrawal exposures allows stress to elicit anxiety after a period of abstinence. Social interaction was used to assess the degree of anxiety induced by 45 min of restraint stress 3, 7, or 14 days after rats were exposed to multiple withdrawals from a chronic 4.5% ethanol diet. Restraint stress reduced social interaction (ie anxiety-like behavior) at 3, but not at 7 or 14 days, after the multiple withdrawals. No anxiety response was observed in animals that received multiple withdrawals without stress or in animals that received stress when exposed only to control liquid diet. Drugs (ie a CRF1-receptor antagonist, a benzodiazepine receptor antagonist, and a 5-HT1A-receptor agonist) previously demonstrated to block the cumulative adaptation, when administered during repeated withdrawals, prevented stress-induced anxiety-like behavior during abstinence. Additionally, these drugs applied prior to stress in the rats previously exposed to the repeated withdrawal protocol, likewise, minimized stress-induced anxiety. The anxiety following stress during abstinence from previous chronic ethanol exposure is indicative of an interaction of stress with the persistent adaptive change caused by repeated withdrawals. Stress eliciting anxiety-like behavior during abstinence from previous ethanol exposures in rats is consistent with stress inducing anxiety during recovery (sobriety) in the alcoholic, a circumstance that can facilitate craving and relapse.     

Increases in anxiety-like behavior induced by acute stress are reversed by ethanol in adolescent but not adult rats

Repeated exposure to stressors has been found to increase anxiety-like behavior in laboratory rodents, with the social anxiety induced by repeated restraint being extremely sensitive to anxiolytic effects of ethanol in both adolescent and adult rats. No studies, however, have compared social anxiogenic effects of acute stress or the capacity of ethanol to reverse this anxiety in adolescent and adult animals. Therefore, the present study was designed to investigate whether adolescent [postnatal day (P35)] Sprague-Dawley rats differ from their adult counterparts (P70) in the impact of acute restraint stress on social anxiety and in their sensitivity to the social anxiolytic effects of ethanol. Animals were restrained for 90 min, followed by examination of stress- and ethanol-induced (0, 0.25, 0.5, 0.75, and 1 g/kg) alterations in social behavior using a modified social interaction test in a familiar environment. Acute restraint stress increased anxiety, as indexed by reduced levels of social investigation at both ages, and decreased social preference among adolescents. These increases in anxiety were dramatically reversed among adolescents by acute ethanol. No anxiolytic-like effects of ethanol emerged following restraint stress in adults. The social suppression seen in response to higher doses of ethanol was reversed by restraint stress in animals of both ages. To the extent that these data are applicable to humans, the results of the present study provide some experimental evidence that stressful life events may increase the attractiveness of alcohol as an anxiolytic agent for adolescents.     

Ginkgo biloba normalizes stress- and corticosterone-induced impairment of recall in rats.

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 has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and side effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg kg(-1)) decreased re-entry latencies in the passive avoidance situation showing thus impairment of recall. Preventive doses of EGB 761 (100 mg kg(-1)), given 30 min before each restraint stress episode or corticosterone injection, abolished cognitive deficits seen in unprotected rats. There was no influence of stress, corticosterone, and EGB 761 on the acquisition of conditioned avoidance responses (CARs).     

Cannabinoids Ameliorate Impairments Induced by Chronic Stress to Synaptic Plasticity and Short-Term Memory

Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.     

Chronic stress alters behavior in the conditioned defensive burying test: role of the posterior paraventricular thalamus

In the present studies, we examined the effects of chronic restraint on behavior in the conditioned defensive burying paradigm, a well-validated test of anxiety. This test is based on the findings that rodents tend to cover or bury the source of a noxious or aversive stimulus. However, little is known about whether prior chronic stress exposure can alter this anxiety-related behavior. In the present study, we examined whether chronic restraint affects indices of behavior in the conditioned defensive burying paradigm. Furthermore, since the posterior division of the paraventricular thalamus (pPVTh) regulates neuroendocrine activity specifically in chronically stressed but not control rats, we hypothesized that the pPVTh may also regulate any chronic stress-induced changes in behavior observed in the defensive burying test. Chronically stressed rats (30-min restraint per day for seven consecutive days) exhibited decreased latency to bury compared to control rats regardless of the presence of lesions suggesting increased reactivity to the shock in these animals. Importantly, pPVTh-lesioned chronically stressed rats exhibited increased duration and height of burying compared to control rats with pPVTh lesions, whereas no differences existed between sham-lesioned control and chronically stressed rats. Since both burying height and duration of burying are considered indices of anxiety in the defensive burying test, the present results suggest that the intact pPVTh may be important in dampening behaviors related to anxiety in chronically stressed rats.     

L-NAME prevents anxiety-like and depression-like behavior in rats exposed to restraint stress

Stressful life events contribute to the development of many neuropsychiatric disorders including depression and anxiety. Animal studies based on the relationship of stress and depression or anxiety are scarce and controversial. Moreover, neither the neurobiological basis of anxiety and depression nor the mechanisms responsible for neurochemical regulation by stressful stimuli are well understood. This study was designed to investigate the possible contribution of both acute (2 h) and chronic (2 h X 15 d) restraint stress in the generation of anxiety and depression, and also to find out whether nitric oxide (NO) has a modulatory role in these behavioral reactions. Elevated plus-maze and forced swimming test (FST) were chosen for assessment of anxiety and depression, respectively, and N(G)-nitro L-arginine methyl ester (L-NAME, 10 mg/kg), a NO synthase (NOS) inhibitor, and L-arginine (50 mg/kg), a NO precursor, were used to evaluate the role of nitrergic system in restraint exposed rats. The results showed that acute and chronic stress caused depression-like and anxiety-like behaviors in rats and the acute inhibition of NOS by L-NAME prevented these acute and chronic stress-induced anxiogenesis and depression. These data lead to the conclusion that stress and NO seem to be involved in the generation of anxiety and depression.     

Mechanism of St. John's wort extract (STW3-VI) during chronic restraint stress is mediated by the interrelationship of the immune,oxidative defense,and neuroendocrine system

Chronic stress is a contributing risk factor for the development of psychiatric illnesses such as anxiety and depression disorders. The aim of the present study was to evaluate the mechanisms of action of the standardized St. John's wort extract (STW3-VI; SJW) in a chronic restraint stress model. Markers of antioxidant capacity such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus and hypothalamus, and plasma levels of ACTH and corticosterone as well as the inflammatory markers IL-6 and TNF-α were determined in rats exposed to chronic restraint stress for 21 consecutive days. In addition, total body and relative organ weights as well as behavioral changes in the open field test were evaluated on the last day. The results show that stressed animals decreased in open field activity compared to unstressed animals, which could be reversed by fluoxetine (10 mg/kg, p.o.) and SJW (125–750 mg/kg, p.o.) treatment. In addition, chronic restraint stress significantly decreased thymus and spleen indices in the stressed control group. However, treating stressed rats with fluoxetine or STW3-VI produced a significant and dose dependent increase in both thymus and spleen indices compared to stressed controls. Additionally, SJW and fluoxetine significantly reduced stress-induced increases in plasma ACTH and corticosterone levels. Furthermore, the administration of SJW significantly reduced the stress-induced increase in TNF-α levels. Our data provide new evidence for the hypothesis that the mechanism of action of STW3-VI is mediated by the interrelationship between the immune, oxidative defense and neuroendocrine system.     

Different effect of desipramine on locomotor activity in quinpirole-treated rats after repeated restraint and chronic mild stress

We have studied the effect of chronic treatment with the tricyclic antidepressant drug desipramine on locomotor activity in rats challenged with the administration of the D2-like dopamine agonist quinpirole, after prolonged exposure to two different stress regimens, repeated restraint stress and chronic mild stress (different stressors randomly presented). These stress schedules have been previously reported to influence in opposite ways the sensitivity to the locomotor response mediated by the stimulation of mesolimbic dopamine receptors. In particular, repeated restraint has been reported to induce an increased response to the locomotor effect of amphetamine, while chronic mild stress has been reported to induce a decreased locomotor response to quinpirole. In the present study, repeated restraint stress failed to influence the locomotor activity after challenge with quinpirole, while chronic mild stress reduced this response. Chronic treatment with desipramine failed to influence this response in the control group, but exerted opposite effects in the two stressed groups. In particular, chronic desipramine reduced locomotor activity in quinpirole-treated rats in the restraint stress group, and increased it in the chronic mild stress group, thus preventing the subsensitivity induced by this stress regimen. The present results, taken together with results from earlier studies, are consistent with the hypothesis that the effect of antidepressants on the sensitivity of the mesolimbic dopamine receptors mediating the locomotor behavioural response tends to be opposite with respect to that exerted by stress, regardless of its direction. However, since we failed to show an increased locomotor activity after quinpirole challenge in the repeated restraint group, this hypothesis remains to be demonstrated. The two stress schedules reduced body weight gain in a similar way, therefore their different effects do not seem to be due to a difference in stress severity. Thus, the observation that both stress schedules reduced body weight gain in a similar way, but only chronic mild stress reduced the sensitivity to the locomotor response to quinpirole, shows that this effect is not an artefact of body weight decrease.     

Depressive state with anxiety in repeated cold-stressed mice in forced swimming tests

The effects of various types of stress and drugs were studied to assess mouse performance in forced swimming tests, following characterization of SART (specific alternation of rhythm in environmental temperature) stress. Immobility time in the test decreased in mice subjected to SART, acute cold and restraint stress. No change was noted due to chronic cold stress or repeated fasting. The shortened time did not recover even 24 hr after the end of SART and chronic restraint stress. The time in SART-stressed mice finally recovered at 5-7 days. Shortening of immobility time in SART-stressed mice was inhibited by diazepam and repeated imipramine but not by lithium carbonate. In chronic restraint-stressed mice, this time was inhibited by repeated lithium carbonate but not diazepam or imipramine. SART stress would thus appear related to anxiety and depression and may be useful for detecting new types of antidepressants.     

Chlordiazepoxide and stress tolerance in rats

Intraperitoneal injections of chlordiazepoxide in rats attenuated the severity of stomach ulcers induced by a single restraint session. However, when the drug was withheld during the last session of a series of repeated restraint treatments, stomach erosions developed in the animals. Vehicle-controls, on the other hand, had adapted to the chronic stress, as indexed by a decline in gastric pathology. The results were discussed in reference to stress adaptation and drug withdrawal effects.     

Sex-specific differences on caffeine consumption and chronic stress-induced anxiety-like behavior and DNA breaks in the hippocampus

Caffeine is widely consumed in beverages and food, and its consumption in high doses is associated with anxiety increase. Stress situations are often associated to coffee consumption, and have a strong influence on oxidative DNA damage. As there are sex-specific differences in many metabolic, neurochemical and behavioral aspects, the aim of this study is to verify the interaction between chronic consumption of caffeine and chronic stress on anxiety and DNA breaks in the hippocampus on male and female rats. Wistar rats were submitted to restraint stress for at least 50 days. The diet consisted of standard rat chow and caffeine 0.3 or 1 g/L in drinking water “ad libitum” as the only drinking source. Controls received tap water. Anxiety-like behavior and DNA breaks in the hippocampus were evaluated. Caffeine consumption and chronic stress increased anxiety-like behavior as well as DNA breaks in the hippocampus of male rats. No effect on these parameters was observed in females. These results may be related to the presence of estradiol, which may have anxiolytic and neuroprotective properties.     

Involvement of septal Cdk5 in the emergence of excessive anxiety induced by stress.

The aim of the present study was to evaluate whether the activation of Cdk5, a protein that has been suggested to participate in higher cognitive functions, is required for the onset of a sensitized anxiety-related behavior induced by stress. The exposure to restraint enhanced both Cdk5 expression in certain subareas of the septohippocampal system, principally in the lateral septum (LS) and septal Cdk5 kinase activity in rats. Behaviorally, restrained wild type mice showed a behavior indicative of enhanced anxiety in the elevated plus maze (EPM). In contrast, unstressed mice and stressed knockout mice, which lacked the p35 protein, the natural activator of Cdk5, displayed similar anxiety-like behavior in the EPM. Finally, the intra-LS infusion of olomoucine - a Cdk5 inhibitor - blocked the enhanced anxiety in the EPM induced by prior stress in rats. All these data provide evidence that septal Cdk5 is required in the emergence of a sensitized emotional process induced by stress.     

Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala

Chronic restraint stress affects hippocampal and amygdalar synaptic plasticity as determined by electrophysiological, morphological and behavioral measures, changes that are inhibited by some but not all antidepressants. The efficacy of some classes of antidepressants is proposed to involve increased phosphorylation of cAMP response element binding protein (CREB), leading to increased expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). Conversely, some studies suggest that acute and chronic stress downregulate BDNF expression and activity. Accordingly, the aim of the current study was to examine total and phosphorylated CREB (pCREB), as well as BDNF mRNA and protein levels in the hippocampus and amygdala of rats subjected to chronic restraint stress in the presence and absence of the antidepressant tianeptine. In the hippocampus, chronic restraint stress increased pCREB levels without affecting BDNF mRNA or protein expression. Tianeptine administration had no effect upon these measures in the hippocampus. In the amygdala, BDNF mRNA expression was not modulated in chronic restraint stress rats given saline in spite of increased pCREB levels. Conversely, BDNF mRNA levels were increased in the amygdala of chronic restraint stress/tianeptine rats in the absence of changes in pCREB levels when compared to non-stressed controls. Amygdalar BDNF protein increased while pCREB levels decreased in tianeptine-treated rats irrespective of stress conditions. Collectively, these results demonstrate that tianeptine concomitantly decreases pCREB while increasing BDNF expression in the rat amygdala, increases in neurotrophic factor expression that may participate in the enhancement of amygdalar synaptic plasticity mediated by tianeptine.     

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization.

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20-120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3-2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to activate the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modified morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.     

Anti-Ulcerogenic Evaluation of the Persian Tooth Brush Tree (Salvadora Persica)

The effect of the lyophilized decoction of Salvadora persica on ulceration induced by ethanol, indomethacin and cold restraint stress was investigated in rats. Pre-treatment tests in rats revealed that the extract possessed significant protective action against ulcers induced by ethanol or stress. The protective effect was not altered by indomethacin, administered as a prostaglandin biosynthesis inhibitor. Salvadora persica shows some increase in gastric mucus with a certain diminution in the ulcer index in cold stress-induced ulcers. However, the drug failed to heal ethanol and indomethacin-induced ulcers.     

Effect of the chronic ingestion of chlorimipramine and desipramine on the hole board response to acute stresses in male rats

The effect of the chronic ingestion of chlorimipramine (CI) or desipramine (DS) on the alterations of hole board behavior caused by a model stress (2 IP injections of physiological saline) and by a short restraint stress (5 min) is analyzed in this study. The experimental groups ingested about 3 mg/kg/24 hr CI or DS for 15 days. Then some experimental and control rats were assigned to control of drug effects on baseline activity. The remaining rats were submitted to saline stress (Experiment I) or restraint stress (Experiment II). The baseline scores of hole board locomotion, head dipping, grooming and defecation were not affected by DS treatment but locomotion slightly increased in the CI treated group. Saline stress impaired significantly head dipping and caused excessive grooming in control rats. The CI treatment induced almost full protection against these behavioral effects of saline stress but DS treatment was ineffective. Restraint stress was found to cause a pronounced inhibition of head dipping as well as a great increase of the scores of grooming in the control group. The CI treatment clearly attenuated these effects of restraint but DS treatment was not effective. The results suggest that male rats treated chronically with CI tolerated both acute stresses better than untreated rats, and that a similar treatment with DS did not provide protection against the effect of such stresses on hole board responding. Inasmuch as CI and DS have different relative potency at noradrenergic and serotonergic systems, it is speculated that this might be in part responsible for their differences as stress protectors.     

St John's wort (Hypericum perforatum) diminishes cognitive impairment caused by the chronic restraint stress in rats.

In this study we tested the hypothesis that St John's wort (Hypericum perforatum) may counteract stress-induced memory impairment. Object recognition test and Morris water maze were used to determine whether administration of H. perforatum (350 mg kg(-1) for 21 days), standardized to 0.3% hypericin content, protects against non-spatial and/or spatial memory impairments due to chronic restraint stress (2h daily for 21 days). A group of rats administered the exogenous corticosterone at the dose of 5 mg kg(-1) daily for 21 days, yielding its similar plasma levels as these observed in stress was run in parallel. In the first experiment all rats were tested for recognition memory in the object recognition test. On the following day, the animals were tested in open field and elevated "plus" maze to control for the contribution of respectively, motor and emotional effects of our treatments to the memory tests. In the second experiment, new group of stressed animals was tested for spatial memory in the water maze. We observed that H. perforatum prevented the deleterious effects of both chronic restraint stress and long-term corticosterone on learning and memory as measured in both, the object recognition and the water maze tests. The herb not only prevented stress- and corticosterone-induced memory impairments, but it significantly improved recognition memory (p<0.01) in comparison to control. These results suggest that H. perforatum has a potential to prevent stress memory disorders.     

Chronic Non-Social Stress Affects Depressive Behaviors But Not Anxiety in Mice

The etiology of most psychiatric disorders is still incompletely understood. However, growing evidence suggests that stress is a potent environmental risk factor for depression and anxiety. In rodents, various stress paradigms have been developed, but psychosocial stress paradigms have received more attention than non-social stress paradigms because psychosocial stress is more prevalent in humans. Interestingly, some recent studies suggest that chronic psychosocial stress and social isolation affects mainly anxiety-related behaviors in mice. However, it is unclear whether chronic non-social stress induces both depression- and anxiety-related phenotypes or induces one specific phenotype in mice. In the present study, we examined the behavioral consequences of three chronic non-social stress paradigms: chronic predictable (restraint) stress (CPS), chronic unpredictable stress (CUS), and repeated corticosterone-HBC complex injection (RCI). Each of the three paradigms induced mild to severe depression/despair-like behaviors in mice and resulted in increased immobility in a tail suspension test. However, anxiety-related phenotypes, thigmotaxis and explorative behaviors, were not changed by the three paradigms. These results suggest that depression- and anxiety-related phenotypes can be dissociated in mouse stress models and that social and non-social stressors might affect brain circuits and behaviors differently.