Chronic Forced Swim Stress Research Articles

Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress

Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.

Cerebral Metabolic Changes in a Depression-like Rat Model of Chronic Forced Swimming Studied by Ex vivo High Resolution 1H Magnetic Resonance Spectroscopy

Many previous in vivo (1)H magnetic resonance spectroscopy (MRS) studies have shown that patients with major depressive disorder (MDD) are associated with perturbations of cerebral metabolism of neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA). In this study, we investigated the changes of cerebral metabolism in a depression-like rat model of chronic forced swimming stress (CFSS). The aims are to further understand the pathophysiological mechanisms underlying CFSS treatment, and to further establish the face and predictive validity of the CFSS model. The results showed that, relative to control, the CFSS rats had significantly reduced Glu, taurine and glutamate + glutamine (Glx) levels in the PFC, and significantly reduced N-acetyl aspartate (NAA) level, Glu level and Glu/GABA ratio in the hippocampus. Taking together, these results suggest that CFSS treatment can induce region-specific changes in the metabolism of Glu. The CFSS model might be used to study antidepressants specifically targeting the central glutamatergic system.

Different effects of chronic forced swim and restraint stress upon the rat spatial learning and memory

Objective To observe the effect of chronic forced swim or restraint stress on the rat's spatial learning and memory performance.Methods Twenty-four adult male Sprague-Dawley rats were randomly divided into three groups:control group(rats receiving neither stress);chronic forced swim stress (FST) group(rats were forced to swim daily for 20 minutes during 14 days);and chronic restraint stress (CRS) group(rats were loosely restrained daily in a transparent plastic cylinder which made the rats could not move freely for 6 hours during 14 days).1,2 or 3 weeks after the final secession of either stress,the navigation test and probe test of Morris water maze were employed to evaluate the rat's spatial learning and memory ability,respectively.Results (1) 1 and 2 weeks after the final stress secession,the averaged escape latency of FST group in the navigation test was significantly shortened [1week:FST (14.56±2.17)s,(17.93±2.08)s,CONTROL(26.12±5.04)s,(25.22±2.80)s,t=11.21 and 7.25,P＜0.05];meanwhile,the averaged ratio of time spent in the target quadrant for the FST group in the probe test was significantly higher than that of the control group(P＜0.05).3 weeks after the final stress secession,there was no significant difference in the escape latencies and the ratio of time spent in the target quadrant between control and FST group.(2) 1 week after the final stress secession,both the averaged escape latency in the navigation test and the averaged ratio of time spent in the target quadrant for the probe test of CRS group were significantly changed when compared with that of the control group (P＜0.05).While 2 or 3 weeks after the final stress secession,these differences disappeared.Conclusion Chronic forced swim enhanced while the chronic low intensity restrain impaired rat's spatial learning and memory.These effects could not last long since the difference disappeared as the rats withdrew from the stress for a relatively long period.Different patterns of chronic stress gave rise to different reversible influences upon the rat's spatial learning and memory. Key words: Stress ; Forced swim ; Chronic restraint ; Navigation test ; Probe test ;

Chronic forced swim stress inhibits ultra-low dose morphine-induced hyperalgesia in rats

Ultra-low doses of morphine (UL-morphine) induce hyperalgesia, which is assumed to be mediated by stimulatory G proteins (G(alphas)) signaling pathway. G(alphas) pathway inhibition and chronic stress both attenuate development of tolerance to analgesic effect of morphine. This study evaluated the effect of chronic stress on UL-morphine-induced hyperalgesia to find out if chronic stress interacts with the G(alphas) signaling pathway. Repeated daily forced swim stress was applied to induce chronic stress. UL-morphine (1 microg/kg, intraperitoneal)-induced hyperalgesia was assessed using the tail-flick test on day 6, in male rats that during days 1-5 received different treatments of swim stress, dexamethasone, swim stress following adrenalectomy (ADX) or swim stress after sham operation. Chronic stress by itself induced hyperalgesia in control and sham-operated rats but inhibited UL-morphine-induced hyperalgesia. In ADX animals, chronic stress did not produce hyperalgesia and could not inhibit UL-morphine-induced hyperalgesia. Chronic dexamethasone produced hyperalgesia but did not change the UL-morphine-induced hyperalgesia. Inhibition of UL-morphine hyperalgesia by chronic stress suggests that chronic stress interacts with the G(alphas) signaling pathway, which is responsible for UL-morphine-induced hyperalgesia. The absence of this effect in the ADX-rats or after repetitive dexamethasone administration demonstrates that hypothalamic-pituitary-adrenal (HPA) axis activation is necessary for controlling UL-morphine-induced hyperalgesia. Finally, the interaction of stress with the G(alphas) signaling pathway may provide an explanation for the inhibitory effect of stress on development of tolerance to the analgesic effect of morphine.

The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress

In the present study, 40 Sprague–Dawley rats were divided into forced swim stress group and controls, with 20 rats in each group (10 for behavioral tests, 10 for protein detection). The forced swim stress group received swim stress for 14 consecutive days, and the controls were stress-free. After stress, 20 rats were tested for behavioral observation using body weight gain, open field, elevated plus-maze and saccharine preference test, and 20 rats were decapitated for protein detection. The extracellular signal-regulated kinase (Erk) and phospho-Erk (P-Erk) in the hippocampus and prefrontal cortex were determined using western blot. It was found that the body weight gain of stressed animals during the 7 stressed days and the 14 stressed days was significantly decreased compared to that of controls. Stressed animals spent less time in open arms and longer time in closed arms. The stressed animals demonstrated decreased locomotor activity and increased grooming in open field. The saccharine solution intake and the ratio of saccharine solution intake to total liquid intake were both decreased in the stressed group. Stressed animals showed decreased P-Erk2 and decreased ratio of P-Erk2 to total Erk2 in the hippocampus and prefrontal cortex, but their Erk1/2 was increased in the prefrontal cortex with no change in hippocampus. The saccharine solution intake positively correlated with the P-Erk2 in the hippocampus and negatively correlated with the Erk2 in the prefrontal cortex. In conclusion, chronic forced swim stress was a good animal model of depression, and it induced depressive-like behavior and decreased P-Erk2 in the hippocampus and prefrontal cortex in rats. The depressive-like behaviors were correlated with decreased phosphorylation of Erk, which suggested that the dysfunction of Erk activity might be one of biological mechanisms underlying depression induced by stress.

Sympatho-adrenomedullary system responses to various chronic stress situations

We studied the effects of four different chronic stressors: isolation, crowding, forced swimming and isolation followed by forced swimming, on the level of plasma noradrenaline (NA) and adrenaline (A), both under basal conditions and in response to acute immobilization and cold as additional stressors. None of these chronic stressors changed basal plasma NA and A concentrations. When chronically isolated rats are exposed to immobilization they show significant elevation of plasma NA and A, but cold stress significantly increases only NA level and not the concentration of A. When animals exposed to chronic crowding, forced swimming and isolation plus forced swimming are exposed to immobilization plasma catecholamine also increases, but less in comparison to the chronically isolated rats. Based on these results, it may be concluded that chronic isolation seems to be a stronger stressor for animals than other chronic stressors. Chronic forced swimming stress and crowding seem to be the weakest stressors, if measured by the activity of sympathoadrenomedullary system. However, daily short-term swimming stress seems to attenuate the effect of chronic isolation on the activity of the sympatho-adrenomedullary system. .

Cellular mechanisms underlying the effects of an early experience on cognitive abilities and affective states

In the present study we investigated the effects of neonatal handling, an animal model of early experience, on spatial learning and memory, on hippocampal glucocorticoid (GR), mineralocorticoid (MR) and type 1A serotonin (5-HT1A) receptors, as well as brain derived neurotrophic factor (BDNF), and on circulating leptin levels, of male rats.MethodSpatial learning and memory following an acute restraint stress (30 min) were assessed in the Morris water maze. Hippocampal GR, MR and BDNF levels were determined immunocytochemically. 5-HT1A receptors were quantified by in vitro binding autoradiography. Circulating leptin levels, following a chronic forced swimming stress, were measured by radioimmunoassay (RIA). Data were statistically analyzed by analysis of variance (ANOVA).ResultsNeonatal handling increased the ability of male rats for spatial learning and memory. It also resulted in increased GR/MR ratio, BDNF and 5-HT1A receptor levels in the hippocampus. Furthermore, leptin levels, body weight and food consumption during chronic forced swimming stress were reduced as a result of handling.ConclusionNeonatal handling is shown to have a beneficial effect in the males, improving their cognitive abilities. This effect on behavior could be mediated by the handling-induced increase in hippocampal GR/MR ratio and BDNF levels. The handling-induced changes in BDNF and 5-HT1A receptors could underlie the previously documented effect of handling in preventing "depression". Furthermore, handling is shown to prevent other maladaptive states such as stress-induced hyperphagia, obesity and resistance to leptin.

Influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats.

We studied the influence of imipramine on the duration of immobility in chronic forced-swim-stressed rats. Both single and chronic administration of imipramine potently shortened immobility in naive rats during forced-swim testing. However, chronic, 14-day forced-swim stress testing blocked the immobility-decreasing effect induced by a single administration of imipramine. When imipramine was administered for 14 days concurrently with forced-swim stress testing, immobility was shortened significantly. From the viewpoint of imipramine's effect, these findings suggest that chronic forced-swim stress testing in rats may be an effective animal model for depression.

Effect of Neonatal Handling and Sex on Basal and Chronic Stress-Induced Corticosterone and Leptin Secretion

Neonatal handling is an experimental paradigm for early experiences. It affects the programming of hypothalamo-pituitary-adrenal (HPA) axis function, known to be sexually dimorphic. Recently leptin, a hormone related to energy balance and secreted mainly by adipocytes, has been implicated in the stress response. We thus determined the effect of neonatal handling on plasma concentrations of corticosterone and leptin of male and female rats under basal conditions and after two consecutive chronic stressors: chronic forced swimming stress and chronic restraint. Handling resulted in lower basal corticosterone levels in both males and females and in a more efficient HPA response, with a large corticosterone surge following the first chronic stressor and a return to basal levels following the second. Handling also resulted in decreased plasma leptin concentrations in males, thus abolishing the sex difference in leptin levels. Furthermore, handling increased body weight while it decreased food intake under basal conditions. Food intake and body weight gain during chronic forced swimming was lower in handled than in non-handled males, while in females these parameters were not influenced by handling. In both males and females, handling resulted in decreased food intake and increased body weight loss during chronic restraint stress. Body weight loss during chronic restraint stress, which is considered an index of maladaptation and ‘depression’, was particularly pronounced in the handled females. Our results also showed that non-handled females had higher corticosterone and lower leptin levels than males under basal conditions and following each of the two chronic stressors. The present work suggests that early experiences, such as the mother–infant relationship, interact with endogenous factors, such as gonadal hormones, to determine the organism’s response to stressful stimuli during adulthood.

Sex differences in the effects of neonatal handling on the animal's response to stress and the vulnerability for depressive behaviour

Neonatal handling is known to affect the programming of the hypothalamic–pituitary–adrenal axis and, as a result, the ability of the organism to respond to stress. We determined the effect of neonatal handling on the animal's response in three animal models of depression, as well as to either (a) acute or (b) chronic forced swimming stress. Neonatal handling resulted in a significant increase in the immobility time in the Porsolt forced swimming test in both sexes, and in the 8-hydroxy-2-(di- n-propylamino) tetralin-induced hypothermia in the males. On the other hand, handling had sex-dependent effects when animals were exposed to a chronic stressor. After exposure to chronic restraint stress, statistically more handled than non-handled females failed to adapt, while no such difference was found in the males. In the chronic forced swimming stress, handled males had shorter immobility times, and higher plasma corticosterone levels, while the opposite held true in the females. Furthermore, neonatal handling significantly decreased basal plasma corticosterone levels in both pre- and post-pubertal animals. Thus, the early experience of handling provides males with a greater capacity to actively face chronic stressors, while in the females it increases their susceptibility to express ‘depressive’ behaviour since they are unable to cope and adopt a ‘passive, despaired’ behaviour.

Chronic forced swim stress of rats increases frontal cortical 5-HT 2 receptors and the wet-dog shakes they mediate, but not frontal cortical β-adrenoceptors

We studied the effects of chronic forced swim stress on 5-HT 2 receptors and β-adrenoceptors in the rat frontal cortex. The number of 5-HT 2 receptors was increased immediately after the last chronic stress, but not after an acute stress. In vivo, the number of wet-dog shakes induced by a 5-HT 2 receptor agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), was increased 24 h after the last chronic stress. However, the concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA), measured by high pressure liquid chromatography (HPLC), were not altered by this stress. Binding sites for [ 3H]CGP-12177, i.e., β-adrenoceptor sites, were unchanged after both the acute and the chronic stress. These results suggest that, in the rat, the chronic forced swim stress increases the number of frontal cortical 5-HT 2 receptors and the number of wet-dog shakes mediated by these receptors, while the number of frontal cortical β-adrenoceptors is not increased by this treatment.

Chronic forced swim stress produces subsensitivity to nicotine

Twice daily injections of saline reduce the thermic response to nicotine in the rat. The authors hypothesized that this was due to the stress of twice-daily handling and injection. However, the injection of saline is not a classic stressor. The hypothesis that stress blunts thermic respinsiveness to nicotine was, therefore, tested using a classic form of chronic inescapable stress. Rats (n = 12) were subjected to a 14-day, twice daily course of inescapable cold water swim stress using a repeated measures design. Thermic responsiveness of nicotine was measured at baseline and every 7 days thereafter for 49 days. The mean response to nicotine (1.0 mg/kg IP) differed significantly across time, F(7,88) = 10.6, p<0.0001. Mean thermic responsiveness (±SEM) decreased from −0.75±0.09 at baseline to −0.41±0.18°C (54.7 % of baseline) following 14 days of forced swim stress. This change was not significant. However, the thermic response to nicotine was −0.14±0.13°C ( p<0.05), +0.55±0.12°C ( p<0.05), and +0.04±0.11°C ( p<0.05) 7, 14, and 21 days following the discontinuation of forced swim stress. The mean response did not differ from baseline 28 days following the last session of forced swim stress. The data suggest that in the recovery phase the animals ceased to be sensitive to nicotine. These findings support the hypothesis that a chronic stressor can produce subsensitivity to nicotine.

Chronic restraint stress does not sensitize a muscarinic mechanism

Describing the neurobiological changes which may explain the link between chronic stressors and the epidemiological association of recurrent episodes of depression in patients with unipolar or bipolar illness is a goal of psychiatric research. Disorders of mood may involve hyperactivity of central muscarinic mechanisms. Chronic forced swim stress and footshock produce supersensitivity to a muscarinic agonist. Chronic prolonged restraint is a severe stressor for the rat and activates the hypothalamic-pituitary-adrenal (HPA) axis. This report presents data suggesting that this stressor does not, unlike forced swim stress and footshock, enhance sensitivity to the hypothermic effects of a muscarinic agonist.