Is immobility of rats in the forced swim test "behavioral despair"?

Rats were forced to swim in a cistern until sinking in order to examine the possible relationship between sinking and immobility which has been reported to reflect "behavioral despair" in the forced swim test. Rats were classified into sinking and non-sinking groups, according to the appearance of sinking behavior over a 2 hr test. The sinking rats showed significantly shorter immobility times during the first 15 min as compared to the non-sinking rats. Therefore, sinking behavior seems to be a sign of emotional behavior such as fear and/or anxiety accompanied by defecation. Discriminant analysis showed that the immobility time during the first 15 min was a prediction of sinking. These findings suggest that the rapidly induced immobility in this forced swim test reflects the possibility of floating behavior in connection with the emotional reaction.     

The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism

The Fawn-Hooded (FH/Wjd) rat is an inbred strain of rat that has been reported to exhibit both high immobility in the forced swim test and high voluntary ethanol intake, measures that have been periodically linked with depression and alcoholism in humans. The present paper will first present a survey of the literature and previously unpublished findings that bear on the question of whether FH/Wjd rats should be considered genetic animal models of depression and alcoholism. Subsequently, behavioral studies of the FH/Wjd rats, the non-drinking ACI/N strain, and their F1 and F2 intercrosses will be described. Under free choice conditions, the FH/Wjd rat drinks up to 6 g/kg 10% ethanol per day. This intake was sufficient to render the rats tolerant to the hypothermic effects of injected ethanol (2.5 g/kg). Rats that had been voluntarily drinking for at least 6 weeks also exhibited withdrawal-induced anxiety in the social interaction, elevated plus maze, and ultrasonic vocalization tasks. The FH/Wjd rat exhibits a 25-30% increase in alcohol intake when the alcohol is returned after a 24-h period of deprivation. It responds to drugs that are effective in humans with a reduction in alcohol intake. Therefore, the FH/Wjd rat meets most of the criteria for an animal model of alcoholism. Chronic antidepressant treatments correct several of the abnormalities exhibited by the FH/Wjd rats, including the exaggerated immobility in the forced swim test. Therefore, the FH/Wjd rats also fulfill some of the criteria for an animal model of depression. On the contrary, inbred ACI/N rats do not drink much alcohol voluntarily and are quite active in the forced swim test. The FH/Wjd and ACI/N rats were intercrossed to obtain the F1 and F2 progenies, which were then tested for alcohol intake and immobility. Alcohol intake and immobility were distributed in different patterns in the F1 and F2 progenies. Alcohol intake was intermediate in the F1 progeny, while immobility was closer to the FH/Wjd parents. In the F2 progeny, chi-square analyses indicated that the distributions were significantly different. In addition, there were no significant litter effects, indicating that maternal effects did not appear to occur. There were also no significant differences among rats with different coat colors, suggesting that the Fawn-Hooded phenotype can be separated from the measures of alcohol intake and immobility. We conclude that the FH/Wjd rat is a genetic animal model of depression and alcoholism, but that the two measures reflective of these states are under separate genetic controls.     

Chronic mild stress impact: Are females more vulnerable?

Despite the knowledge that women are more susceptible than men to stress-related mental illness, such as major depression, there is no comprehensive estimation of the role of gender in the detrimental effects of chronic stress that might cause depression. Sex differences regarding the association of behavioral parameters with serotonergic and hypothalamic-pituitary-adrenal axis activities were investigated in the chronic mild stress model of depression. Additionally, the impact of chronic mild stress exposure on an additional/novel short-term stressful procedure, such as the forced swim test was examined in male and female rats. Female rats were found to be more vulnerable to chronic mild stress and that was depicted with disruption of sucrose intake, decreases in open field activity, increased corticosterone levels, alteration in estrous cycle and decreased serotonergic activity in hippocampus and hypothalamus. On the contrary, in males the current chronic mild stress protocol elicited only behavioral changes, such as disruption in sucrose intake and decreased open field activity. Interestingly, in response to forced swim test, females previously subjected to chronic mild stress, were found to cope better by exhibiting increased active behavior in the second forced swim test session and higher hypothalamic serotonergic activity in comparison with corresponding males. On the other hand, males were more affected by previous chronic mild stress exposure and that was manifested by decreased active behavior in the first forced swim test session and increased corticosterone levels following second forced swim test session. These data indicate that although females are more vulnerable in the application of chronic mild stress than males, in response to an additional-novel stressor (forced swim test) they show better response. Therefore, both sex/gender and combination of stressful procedures should be carefully considered in the study of the pathophysiology of stress-related mental illnesses.     

Failure of neonatal clomipramine treatment to alter forced swim immobility: chronic treadmill or activity-wheel running and imipramine

We examined whether chronic running on a treadmill or activity wheel would attenuate the increased swim immobility that has been reported after neonatal clomipramine (CLI) treatment. Male Sprague-Dawley pups (N = 60) were injected with the monoamine reuptake inhibitor clomipramine hydrochloride (40 mg/kg per day i.p.) from 8 to 21 days of age. Another group (N = 12) received saline vehicle. At age 4 weeks, the CLI pups were randomly assigned to experimental conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary that received the antidepressant drug imipramine hydrochloride (10 mg/kg twice daily) during the last 10 days of the experiment; (4) activity wheel + imipramine; (5) treadmill running (30 m/min for 1 h at 0 degrees incline, 6 days/week). At age 16 weeks, rats underwent the Porsolt swim test 48 h after the last imipramine injection and/or the last exercise session. The increase in swim immobility among CLI-treated rats was small (one quarter of SD) and not statistically significant (p>0.10). The results are not consistent with our previous finding of antidepressant-like effects of activity-wheel running based on brain noradrenergic adaptations and enhanced male copulatory performance after neonatal CLI treatment. The lack of change in swim performance after clomipramine questions the generalizability of the CLI model of depression and the validity of the forced swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic activity-wheel running.     

Periodic abstinence enhances nociception without significantly altering the antinociceptive efficacy of spinal morphine in the rat

Affective disorders are more common in women. The forced swim test acts like a depressive stimulus. Hippocampus and frontal cortex 5-HT_1A receptors of female and male Wistar rats subjected to the forced swim test were compared with a sham group. The forced swim test diminishes (P<0.05) the hippocampus ³H-8OH-DPAT bound in the female rats (184±16 fmol/mg protein) with respect to the male rats (309±41 fmol/mg protein) and to the female sham rats (255±20 fmol/mg protein). The forced swim test increases the frontal cortex 5-HT_1A receptors in the female rats with respect to the female sham group (40.4±5 versus 24.7±4 fmol/mg protein, P<0.05). An increased sensibility of the 5-HT_1A receptors to depressive-stimulus may be one mechanism underlying the higher prevalence of depression in female.     

Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats

A rat model of depression has been recently developed using exogenous corticosterone (CORT) administration. This study aimed to examine the antidepressant-like effect and the possible mechanisms of curcumin in a CORT-induced depression model in rats. The results showed that 3-week CORT injections caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Repeated CORT injections also significantly decreased brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex of the rats. Treatment of the rats with curcumin significantly suppressed the depression-like behavior and the decrease in brain BDNF levels induced by the repeated CORT injections. The results suggest that curcumin produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex.     

Swim test immobility in a genetic rat model of depression is modified by maternal environment: a cross-foster study

The Flinders sensitive line (FSL) genetic animal model of depression exhibits marked immobility during forced swimming, an accepted index of depressive like behavior in rodent depression models. The present experiment tested the hypothesis that swim test behavior in the FSL rats is influenced in part by early experience, specifically maternal environment. Male FSL and control Flinders resistant line (FRL) pups were cross fostered onto dams of the same or complementary strain. Nest quality and dam behavior during pup retrieval were measured on PN5 and PN8, and swim test behavior assessed in the adult males on PN60. FSL rats reared by foster FRL dams were significantly less immobile than FSL rats raised by FSL dams, but still significantly more immobile that the two FRL groups, which did not differ from each other. FSL dams took significantly longer to retrieve their pups and dropped them more often than the FRL control dams. Moreover, strain differences in maternal retrieval behavior significantly predicted later swim test immobility in the FSL animals. These findings suggest that swim test immobility in the FSL rats is modified by maternal environment. In contrast, the FRL control rats were relatively insensitive to the influence of maternal environment. The FSL model offers promise for understanding the interactions of genetic vulnerabilities and environmental influences in the etiology of clinical depression.     

Antidepressive-like effects of electroacupuncture in rats

Here, we investigate the effects of electroacupunture on the depressive-like symptoms in learned helplessness and forced swim tests in rats. Electroacupuncture stimulation (EA) was provided at ST-36 (Zusanli) and SP-6 (Sanyinjiao) acupoints. A positive control group was treated with imipramine. To verify the effects of EA over serotonergic system, other additional groups received daily, for three days, p-chlorophenylalanine and after two days, were submitted to behavioral tests. EA, like imipramine, enhanced the successful active avoidance in the learned helplessness and diminished the time spent in immobility position in the forced swim test, without affecting the number of squares crossed in the open field test. The administration of p-chlorophenylalanine abolished the antidepressive-like effect of EA. EA generates a clear antidepressant effect in two different animal models of depression, and this effect is related, at least in part, to the serotonergic system.     

Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats

We studied the long term effects of neonatal stress in female rats and subsequent responses to stress when adults. Female rats that experienced maternal separation (MS) showed in adulthood depressive-like behavior in the forced swimming test and cognitive impairments in the novel object recognition test, which were reverted by the glucocorticoid receptor antagonist mifepristone or the beta-adrenoceptor antagonist propranolol. Markers of HPA axis (corticosterone levels, CRF mRNA levels in the paraventricular nucleus and glucocorticoid receptor density in the hippocampus) were altered by MS, suggesting that an altered HPA axis function may be associated to behavioral and cognitive deficits in MS female rats. In addition, MS rats were found to be more vulnerable to chronic stress than controls as shown by decreases in open field activity, increases in immobility time in the forced swim test, and changes in markers of HPA axis (decreases in the density of glucocorticoid receptors). These present findings are discussed in terms of gender differences in adulthood.     

Chronic corticosterone administration from adolescence through early adulthood attenuates depression-like behaviors in mice

There is evidence that depression may have a different neural basis at different ages. Although chronic stress and elevated glucocorticoid levels have been demonstrated to lead to the emergence of mood disorders, it remains unclear how moderate elevation of glucocorticoid levels in young animals influences depression-like behaviors and brain functions. To address this issue, the present study examines how chronic corticosterone (CORT) administration during adolescence and early adulthood influences depression-like behaviors, hypothalamic-pituitary-adrenal (HPA) axis response and hippocampal cell proliferation. Male mice were chronically administrated with CORT drinking water (20mg/L) during adolescence. After two months of treatment, serum CORT levels were measured using enzyme immunoassay. Hippocampal glucocorticoid and mineralocorticoid receptors were characterized using Western blot. Tail suspension and forced swim tests were used to assess depression-related behaviors in mice. Immunohistochemistry was performed to measure bromodeoxyuridine (BrdU) incorporation in order to assess cell proliferation in the hippocampus. Our results suggest that chronic CORT administration induced a mild but not significant elevation in basal CORT levels and attenuated the physiological responses to stress. Chronic CORT administration also reduced expression of the hippocampal mineralocorticoid receptor and decreased immobility time in both the tail suspension test and the forced swim test. Moreover, chronic CORT administration increased the BrdU immunoreactivities in the hippocampus. Taken together, these findings suggest that chronic mild elevation by CORT administration during the adolescence and early adulthood attenuates depression-like behaviors.     

Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation

This study was conducted to examine the pathophysiologic mechanisms of long-term adverse effects by neonatal maternal separation on neurobehaviors of the offspring. Sprague-Dawley pups were separated from dam daily for 180min during the first 2 weeks of life (MS) or undisturbed (NH), and subjected to behavioral sessions for ambulatory activity, forced swim, and elevated plus maze tests at 2 months of age. Serotonin reuptake transporter (5-HTT) mRNA levels in the raphe nucleus and the contents of serotonin (5-HT) and its metabolite 5-hydroxyindol acetic acid in the raphe and the hippocampus were examined as well. Ambulatory counts decreased and immobility duration in swim test increased in MS rats compared with NH rats. MS rats spent more time in the closed arms, less time in the open arms, of elevated plus maze, compared to NH rats. The hippocampal contents of 5-HT and the raphe expression of 5-HTT mRNA were decreased in MS rats compared with NH rats. These results suggest that neonatal maternal separation may result in the development of depression- and/or anxiety-like behaviors in later life, in which the long-term alterations in 5-HTergic neurotransmission may take a role.     

Maudsley reactive and nonreactive rats in the forced swim test: comparison in fresh water and soiled water.

Maudsley reactive (MR) and nonreactive (MNRA) and Sprague-Dawley (SD) male rats were tested for their immobility response in the forced swim test when the water was fresh or soiled by a rat of the same or other strain. For all strains, rats tested in soiled water were less immobile than rats in fresh water. The three strains did not differ as producers of soiling substance, but did differ in their response to it. The MR strain was least responsive, whereas the MNRA and SD did not differ from one another. These results support a previous study suggesting that MR rats are more immobile than MNRA rats in the forced swim test. The interpretation of these findings regarding the use of the Maudsley rat strains as an animal model for studying anxiety and/or depression is discussed.     

柚皮苷通过激活小鼠海马脑区mTOR信号通路发挥抗抑郁作用

目的:观察柚皮苷(NRG)对慢性不可预知应激(CUS)模型小鼠抑郁样行为及海马脑区mTOR信号通路的影响,探讨柚皮苷抗抑郁作用的机制.方法:将雄性C57BL/6小鼠随机分为4组:对照组(control)、柚皮苷处理组(NRG)、CUS处理组(CUS)、CUS和柚皮苷联合处理组(CUS+NRG).用糖水偏好实验和强迫游泳...     

天麻素对CUS大鼠抑郁样行为及IL-1β和IL-6水平的影响

目的:探讨天麻素对慢性不可预见应激(CUS)大鼠抑郁样行为的改善作用及对炎症因子IL-1β、IL-6表达的影响。方法:将40只SD大鼠随机分为对照组(Sham),模型组(CUS),模型(CUS)+天麻素低、中、高剂量组,每组8只。对照组每天腹腔注射生理盐水(1 ml/kg),连续14 d;模型组接受CUS造模,并且在造模结束后每天腹腔注射生理盐水(1 ml/kg),连续14 d;模型+天麻素低、中、高剂量组在CUS造模结束后每天腹腔注射不同剂量的天麻素(50、100或者200 mg/kg),持续14 d。随后,通过糖水偏好实验和强迫游泳实验检测各组大鼠的抑郁样行为,在行为学检测结束后处死大鼠,通过ELISA检测海马和血清中IL-1β、IL-6水平变化情况。结果:(1)慢性不可预见应激(CUS)可以导致明显的抑郁样行为,包括糖水偏好减少(P0.05)和强迫游泳不动时间增加(P0.01),CUS组大鼠海马及血浆的IL-1β、IL-6水平明显升高(P0.01)。(2)一定剂量(100和200 mg/kg)天麻素干预可以缓解CUS大鼠的抑郁行为,CUS与CUS+GAS(M)组(P0.05)以及CUS与CUS+GAS(H)组之间(P0.01)存在显著性差异。(3)中高剂量的天麻素可以恢复CUS大鼠海马和血清的IL-1β、IL-6水平,CUS与CUS+GAS(M)组(P0.05)以及CUS与CUS+GAS(H)组之间(P0.05)的IL-1β、IL-6水平存在显著性差异。结论:天麻素可以缓解CUS模型大鼠抑郁样行为,抑制CUS模型大鼠的IL-1β、IL-6水平升高。     

Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats

The forced swim test (FST) has been considered as a pharmacologically valid test of the depressive syndrome in rodents. However, few studies have focused on neurochemical and behavioral responses during FST in both male and female rats. Thus, we investigated certain behavioral and neuroendocrine responses as well as the serotonergic activity after the application of FST in both sexes. Our data show that the duration of immobility was increased in both male and female rats during the 2nd session of the FST. Sex differences are observed in some behavioral responses, such as head swinging that is mostly present in male rats. In female rats FST induced a decrease in serotonergic activity in hippocampus and hypothalamus while in male rats it induced an increase in serotonergic activity in hypothalamus. Corticosterone serum levels were elevated in both sexes. However, hippocampal GR mRNA levels tended to be increased in males and females respectively. Moreover, hypothalamic serotonin (5-HT)1A mRNA levels were decreased in female rats while in male rats hippocampal 5-HT1A mRNA levels were increased. These data have shown that FST induces "depressive like symptoms" in both sexes and provide evidence that sex differences characterize certain behavioral aspects in the FST. Notably, hippocampal and hypothalamic serotonergic activity has been differentially modified in male rats compared with female rats and these neurochemical findings could be relevant to the differentiated expression of 5-HT1A receptor. Hypothalamic-pituitary-adrenal axis activity was also affected by FST application in a sex specific manner. The present results support that FST induced behavioral, neurochemical and neurobiological alterations, which are sex dependent.     

GSK650394对慢性应激抑郁症模型大鼠行为及海马神经营养的调节作用

目的探讨血清和糖皮质激素调节蛋白激酶1(SGK1)抑制剂GSK650394对抑郁症模型大鼠抑郁样行为及海马神经营养的调节作用。方法将SD大鼠随机分为对照组、抑郁模型(慢性温和不可预见性应激加孤养)组、GSK650394(2.8 g/L,按1 mL/kg腹腔注射)干预组;采用强迫游泳、糖水消耗、Morris水迷宫实验观察模型动物的情绪行为变化;用ELISA检测大鼠海马血浆和血清中皮质酮(CORT)、5-羟色胺(5-HT)、去甲肾上腺素(NE)含量;用Western blot检测海马中脑源性神经营养因子(BDNF)、神经营养素3(NT-3)、神经生长因子(NGF)的表达。结果与对照组比较,模型组大鼠蔗糖水偏食度显著降低、游泳不动时间增加(P<0.01)、逃避潜伏期(EL)、目标象限的潜伏时间(Lat.T)均显著延长(P<0.05或P<0.01);血浆CORT显著升高(P<0.01)、血清5-HT、NE和海马NT-3、BDNF、NGF表达显著降低(P<0.05或P<0.01)。与模型组比较,GSK650394可显著增加蔗糖水偏食度、降低游泳不动时间(P&l...     

Lack of depression-like effects of saccharin deprivation in rats: forced swim test, differential reinforcement of low rates and intracranial self-stimulation procedures

In humans and laboratory animals, drug withdrawal often is associated with depression-like behaviors. In the present study, rats had unlimited free-choice access to water and a saccharin-containing solution before being subjected to repeated episodes of saccharin deprivation. Saccharin deprivation (1) reduced immobility time in the forced swim test, (2) increased reinforcement rate in rats trained to lever-press under the differential reinforcement of a low-rate (72-sec) schedule of food reinforcement, and (3) lowered intracranial self-stimulation thresholds in a discrete-trial current titration procedure. Taken together, these findings suggest that deprivation from a nondrug reinforcer, saccharin, is not associated with depression-like behaviors. In contrast, saccharin-deprived rats demonstrated improved performance in the behavioral paradigms used here.     

Ovarian hormone withdrawal-induced "depression" in female rats

Approximately 15% of child-bearing women develop postpartum depression (PPD), and many women with PPD experience anxious symptoms. It has been proposed that PPD is precipitated by the dramatic decline in reproductive hormones that occurs just after childbirth. To examine this hypothesis, ovariectomized female Sprague-Dawley rats underwent a hormone-simulated pregnancy (HSP) regimen; during the subsequent hormone withdrawal period, rats were tested in the forced swim test or elevated plus-maze, animal models of depression and anxiety, respectively. The HSP regimen consisted of injections with progesterone and escalating doses of estradiol benzoate for 22 days; control rats received daily vehicle injections. One, two, four or seven days after the last hormone injection, separate groups of rats were tested once on either the forced swim test or the elevated plus-maze. To examine any hormone withdrawal-induced changes in activity levels, spontaneous locomotor activity was measured at the same time points. At 2 and 4 days after the last hormone injection, HSP-treated females displayed significant increases in immobility relative to vehicle-treated females in the forced swim test. Behavior on the elevated plus-maze did not differ between the HSP and control groups at any of the withdrawal time points. There were also no differences in spontaneous locomotor activity between the HSP and control females at any of the withdrawal time points. The results of this study suggest that postpartum hormone withdrawal may contribute to depressive symptoms experienced after giving birth, and that the HSP-hormone withdrawal protocol may provide a useful animal model of PPD.     

Nortriptyline mediates behavioral effects without affecting hippocampal cytogenesis in a genetic rat depression model

A prevailing hypothesis is that neurogenesis is reduced in depression and that the common mechanism for antidepressant treatments is to increase it in adult hippocampus. Reduced neurogenesis has been shown in healthy rats exposed to stress, but it has not yet been demonstrated in depressed patients. Emerging studies now indicate that selective serotonin reuptake inhibitors can, exert behavioral effects without affecting neurogenesis in mice. Here we extend our previous findings demonstrating that the number of BrdU positive cells in hippocampus was significantly higher in a rat model of depression, the Flinders Sensitive Line (FSL) compared to the control strain the Flinders Resistant Line (FRL). We also show that chronic treatment with the tricyclic antidepressant nortriptyline exerts behavioral effects in the Porsolt forced swim test without affecting hippocampal cell proliferation in the FSL model. These results strengthen the arguments against hypothesis of neurogenesis being necessary in etiology of depression and as requisite for effects of antidepressants, and illustrate the importance of using a disease model and not healthy animals to assess effects of potential therapies for major depressive disorder.     

Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection

Background

Previously, we examined the antidepressant effects of Nelumbinis Semen (NS). In this study, we assessed the anti-depressant effects of NS in the forced swimming test and chronic mild stress (CMS) models of depression and its oral toxicity in rats and dogs.

Methods

In the forced swimming test, NS was intraperitoneally injected before 24?h, 5?h and 1?h of forced swimming test. And the rats were forced to swim for 5?min, the duration of immobility was observed. In CMS models, animals were exposed to a variety of CMS for 8?weeks in order to induce depression-like symptoms. They were treated with NS for the last four weeks of the 8-week CMS and then an open field test was conducted. The anti-depression effects were evaluated based on a measured index, which consisted of visiting counts, start latency, rearing number and grooming time. In the toxicological studies, NS was administered to rats by gavages for 13?weeks at doses of 0, 500, 1000, and 2000?mg/kg/day. To assess the toxicity of NS in beagle dogs, NS was administered orally for 28?days at doses of 0, 500, 1000, 2000 and 4000?mg/kg/day.

Results

400?mg/kg of NS had the lowest immobility times in forced swimming test. And NS significantly reversed the decreased visiting counts, rearing number and grooming time caused by CMS. In addition, NS treatment significantly decreased the start latency. No treatment-related toxicity was detected during 13?weeks administration in rats and 28?days administration in dogs.

Conclusions

Based on the results of this study and previous reports that have examined the anti-depressive effects of NS, NS holds great promise for use in the treatment of depression without causing any adverse effects or toxicities.