Behavior In Forced Swim Test Research Articles

Behavioral effects of saredutant, a tachykinin NK2 receptor antagonist, in experimental models of mood disorders under basal and stress-related conditions

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.

Oral treatment with ACCUTANE ® does not increase measures of anhedonia or depression in rats

Reports of depression and/or suicide with ACCUTANE ® (13- cis-retinoic acid (13- cis-RA)) use prompted studies in a rodent model to ascertain its potential effects. Previously, there were no effects on measures of anhedonia (intake of a saccharin-flavored solution) and depression (forced swim test (FST) behaviors) in rats treated with 7.5 or 22.5 mg/kg 13- cis-RA [S.A. Ferguson, F.J. Cisneros, B. Gough, J.P. Hanig, K.J. Berry, Chronic oral treatment with 13- cis-retinoic acid (isotretinoin) or all- trans-retinoic acid does not alter depression-like behaviors in rats, Toxicol. Sci. 87 (2005) 451–459.]. Here, dose and temporal thresholds were investigated by increasing the maximum 13- cis-RA dose to 30 mg/kg, extending treatment duration, and measuring behaviors repeatedly. Beginning on post-natal day 59, male and female Sprague–Dawley rats were gavaged with soybean oil, 7.5 or 30 mg/kg/day of 13- cis-RA for approximately 19 weeks. FST behaviors were measured after 24, 82, and 131 treatment days and saccharin intake (0.03% solution) was measured at baseline and after 14, 35, 56, and 112 treatment days. Body weight and food intake were not altered by treatment. FST durations of swim, climb/struggle, and immobility were unaffected by 13- cis-RA at any time during treatment. More males than females required “rescue” in the FST but there was no treatment effect on number of rats requiring early removal. 13- cis-RA treatment had no effects on saccharin intake at any time. Given that the 7.5 mg/kg dose produces serum levels which parallel those of humans [S.A. Ferguson, P.H. Siitonen, F.J. Cisneros, B. Gough, J.F. Young, Steady state pharmacokinetics of oral treatment with 13- cis-retinoic acid or all- trans-retinoic acid in male and female adult rats, Basic Clin. Pharmacol. Toxicol 98 (2006) 582–587.], these results are quite relevant. Combined with previous results, these results provide further evidence that 13- cis-RA does not produce behavioral alterations indicative of depression in rats.

Developmental Exposure to Methylmercury Alters Learning and Induces Depression-like Behavior in Male Mice

To investigate the long-term effects of developmental exposure to methylmercury (MeHg), pregnant mice were exposed to at 0.5 mg MeHg/kg/day via drinking water from gestational day 7 until day 7 after delivery. The behavior of offspring was monitored at 5-15 and 26-36 weeks of age using an automated system (IntelliCage) designed for continuous long-term recording of the home cage behavior in social groups and complex analysis of basic activities and learning. In addition, spontaneous locomotion, motor coordination on the accelerating rotarod, spatial learning in Morris water maze, and depression-like behavior in forced swimming test were also studied. The analysis of behavior performed in the IntelliCage without social deprivation occurred to be more sensitive in detecting alterations in activity and learning paradigms. We found normal motor function but decreased exploratory activity in MeHg-exposed male mice, especially at young age. Learning disturbances observed in MeHg-exposed male animals suggest reference memory impairment. Interestingly, the forced swimming test revealed a predisposition to depressive-like behavior in the MeHg-exposed male offspring. This study provides novel evidence that the developmental exposure to MeHg can affect not only cognitive functions but also motivation-driven behaviors.

Enriched environment treatment counteracts enhanced addictive and depressive-like behavior induced by prenatal chronic stress

Prenatal stress can cause many long-term behavior changes in offspring, but whether prenatal stress can alter addictive behavior in offspring and postnatal enriched environment treatment (EE) can restore these changes are unknown. We reported here that prenatal chronic stress (10 unpredictable, 1 s, 0.8 mA foot-shocks per day during gestational days 13–19) enhanced morphine-induced (10 mg/kg, s.c., per day, 6 consecutive days) place preference. Moreover, prenatal chronic stress caused higher depressive-like behavior in forced swimming test in adult offspring. However, enriched environment housing treatment on postnatal days 22–52 counteracted both the abnormal behaviors alterations. This work observed a phenomenon that might contribute to the understanding of clinically important interactions among addiction, prenatal stress and enriched environment treatment. Postnatal enriched environment treatment might be an important therapeutic intervention in preventing the prenatal stress-induced addictive disorders.

Leptin: a potential novel antidepressant.

Leptin, a hormone secreted from adipose tissue, was originally discovered to regulate body weight. The localization of the leptin receptor in limbic structures suggests a potential role for leptin in emotional processes. Here, we show that rats exposed to chronic unpredictable stress and chronic social defeat exhibit low leptin levels in plasma. Systemic leptin treatment reversed the hedonic-like deficit induced by chronic unpredictable stress and improved behavioral despair dose-dependently in the forced swim test (FST), a model widely used for screening potential antidepressant efficacy. The behavioral effects of leptin in the FST were accompanied by increased neuronal activation in limbic structures, particularly in the hippocampus. Intrahippocampal infusion of leptin produced a similar antidepressant-like effect in the FST as its systemic administration. By contrast, infusion of leptin into the hypothalamus decreased body weight but had no effect on FST behavior. These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders.

Decrease of immobility behavior in forced-swimming test and immune system enhancing effect of traditional medicine Gamisipjundaebo-tang

Gamisipjundaebo-tang (GSDBT) has been used for the purpose of development of physical strength. In the present study, we investigated the immune enhancing effect induced by GSDBT. We investigated the anti-immobility effect of GSDBT via a forced-swimming test and blood biochemical parameters related to fatigue, glucose, blood urea nitrogen, lactic dehydrogenase, creatine kinase, and total protein. GSDBT (0.1 and 1 g/kg) was orally administered to mice for 14 days. After 7 and 14 days, as assessed through a forced-swimming test, immobility time was decreased in the GSDBT-administrated group (0.1 and 1 g/kg) in comparison with the control group. In addition, after 8 days, the contents of glucose and lactate dehydrogenase in the blood serum were increased, and contents of blood urea nitrogen were decreased in the GSDBT-administrated group. After 15 days, the contents of glucose were increased, and the contents of lactate dehydrogenase and blood urea nitrogen were decreased in the GSDBT-administrated group. However, it had no effect on the elevation of creatine kinase and total protein level. We also investigated the effect of GSDBT on the production of cytokines in human T-cell line, MOLT-4 cells, and splenocytes. GSDBT significantly increased interferon (IFN)-γ and interleukin (IL)-2 levels compared with the media control but did not affect IL-4. GSDBT increased the protein expression of IFN-γ in MOLT-4 cells. These results suggest that GSDBT may be useful in immune function improvement and may also have antifatigue properties.

Sex- and lineage-specific inheritance of depression-like behavior in the rat.

The Wistar-Kyoto (WKY) rat exhibits physiological and behavioral similarities to endophenotypes of human depression. In the forced swim test (FST), a well-characterized antidepressant-reversible test for behavioral despair in rodents, WKYs express characteristics of behavioral despair; increased immobility, and decreased climbing. To map genetic loci linked to behavior in the FST, we conducted a quantitative trait loci (QTL) analysis of the segregating F2 generation of a WKY x Fisher 344 (F344) reciprocal intercross. Using linear-model-based genome scans to include covariate (sex or lineage)-by-QTL interaction effects, four significant QTL influencing climbing behavior were identified. In addition, we identified three, seven, and two suggestive QTL for climbing, immobility, and swimming, respectively. One of these loci was pleiotropic, affecting both immobility and climbing. As found in human linkage studies, several of these QTL showed sex- and/or lineage-dependent effects. A simultaneous search strategy identified three epistatic locus pairs for climbing. Multiple regression analysis was employed to characterize the joint contributions of these QTL and to clarify the sex- and lineage-dependent effects. As expected for complex traits, FST behavior is influenced by multiple QTL of small effect, each contributing 5%-10%, accounting for a total 10%-30% of the phenotypic variance. A number of loci mapped in this study share overlapping candidate regions with previously identified emotionality QTL in mice as well as with susceptibility loci recognized by linkage or genome scan analyses for major depression or bipolar disorder in humans. The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders.

Hippocampal 3α,5α-THP may alter depressive behavior of pregnant and lactating rats

The 5α-reduced metabolite of progesterone (P), 5α-pregnan-3α-ol-20-one (3α,5α-THP), may mediate progestins' effects to reduce depressive behavior of female rats in part through actions in the hippocampus. To investigate, forced swim test behavior and plasma and hippocampal progestin levels were assessed in groups of rats expected to differ in their 3α,5α-THP levels due to endogenous differences (pregnant and postpartum), administration of a 5α-reductase inhibitor (finasteride; 50 mg/kg sc), and/or gestational stress [prenatal stress (PNS)], an animal model of depression. Pregnant rats had higher plasma and hippocampal 3α,5α-THP levels and less depressive behavior (decreased immobility, increased struggling and swimming) in the forced swim test than did postpartum rats. Finasteride, compared to vehicle-administration, reduced plasma and hippocampal 3α,5α-THP levels and increased depressive behavior (increased immobility, decreased struggling and swimming). PNS was associated with lower hippocampal, but not plasma, 3α,5α-THP levels and increased swimming compared to that observed in control rats. Together, these data suggest that 3α,5α-THP in the hippocampus may mediate antidepressive behavior of female rats.

Selectively bred Wistar-Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants.

The Wistar-Kyoto (WKY) rat strain demonstrates endogenous hormonal and behavioral abnormalities that emulate many of those found in symptom-presenting depressive patients. Evidence suggests that the WKY strain may harbor heterogeneity not found in other inbred strains, including greater behavioral and genetic variability. We took advantage of this variability and selectively bred WKY for 'depressive' behavior using immobility in the forced swim test (FST) as a functional selector. Successive generations of selective breeding resulted in rats that exhibited the extremes of immobility in the FST: 'WKY most immobile' (WMI) and 'WKY least immobile' (WLI). Male WMI rats also showed significantly decreased activity in the open field test (OFT). Plasma corticosterone (CORT) response to restraint stress was significantly lower and less variable in WMI compared to WLI males. Subacute treatment of males with several classes of antidepressant had different effects on FST behavior in the two substrains. Both desipramine (10 mg/kg body weight), a tricyclic antidepressant, and phenelzine (7.5 mg/kg), a monoamine oxidase inhibitor, significantly and drastically decreased FST immobility in WMI. In contrast, WLI showed a limited response to these antidepressants. Neither substrain responded to fluoxetine (10 mg/kg), a selective serotonin reuptake inhibitor. These data show that selective breeding of WKY rats has resulted in two substrains with reduced variability and differing responsiveness to antidepressants, which represent a novel means to dissect the molecular mechanisms underlying depressive behavior.

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto × Fisher 344 cross

Depression is a heritable disorder that is often precipitated by stress. Abnormalities of the stress-reactive hypothalamic-pituitary-adrenal (HPA) axis are also common in depressed patients. In animal models, the forced swim test (FST) is the most frequently used test of depressive-like behavior. We have used a proposed animal model of depression, the Wistar Kyoto (WKY) rat, to investigate the relationship as well as the mode of inheritance of FST behaviors and HPA measures. Through reciprocal breeding of WKY and F344 parent strains and brother-sister breeding of the F1 generation, we obtained 486 F2 animals. Parent, F1 and F2 animals were tested in the FST. Blood samples were collected for determination of basal and stress (10-min restraint) plasma corticosterone (CORT) levels, and adrenal weights were measured. We found that all measures were heritable to some extent and that this heritability was highly sex dependent. Both correlation and factor analyses of the F2 generation data demonstrate that FST behavior and HPA axis measures are not directly related. Thus, the underlying genetic components of depressive-like behavior and HPA axis abnormalities are likely to be disparate in the segregating F2 generation of a WKY x F344 cross.

Changes in Progesterone Metabolites in the Hippocampus Can Modulate Open Field and Forced Swim Test Behavior of Proestrous Rats

The purpose of these experiments was to test the hypothesis that attenuating the endogenous increase of the 5α-reduced progesterone metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) in the hippocampus will alter anxiety and depression behavior of proestrous rats. In Experiment 1, anxiety (open field) and depression (forced swim test) behavior was compared of rats that should have high (proestrous) and low (diestrous and male rats) endogenous hippocampal 3α,5α-THP. Proestrous rats exhibited more anxiolytic-like (increased central entries in the open field) and anti-depressant-like (less immobility in the forced swim test) behavior than diestrous or male rats. In Experiments 2 and 3, respectively, systemic and intrahippocampal finasteride, a 5α-reductase inhibitor which attenuates progesterone's metabolism to 3α,5α-THP, versus vehicle administration to proestrous rats was compared for effects on open field and forced swim test behavior. Systemic or intrahippocampal finasteride decreased central entries in the open field and increased immobility in the forced swim tests compared to vehicle administration. In Experiment 4, the effects of systemic and intrahippocampal finasteride vs vehicle administration on hippocampal 3α,5α-THP of proestrous rats was examined. Finasteride, SC or intrahippocampally, reduced 3α,5α-THP in the hippocampus compared to vehicle administration. Together these data suggest that variations in 3α,5α-THP levels in the hippocampus may mitigate proestrous changes in anxiety and depressive behavior of cycling rats.

An automated analysis of rat behavior in the forced swim test

The Porsolt forced swim test (FST) is a commonly used paradigm to evaluate antidepressant activity of drugs. This test is based on visual measurement of the rat's floating time (FT) in a tank filled with water. Here, we present an automated, accurate and faster method for estimating FT by the distance moved (DM) by the animal via the use of the Ethovision software in three separate experiments. Experiment 1 investigated the effect of varying delays (24-h and 7-day) between pretest and test on FT and DM. Experiment 2 aimed at examining the effects of a 2-day withdrawal period in rats sensitized to amphetamine and cocaine, on FT and DM. Finally, Experiment 3 looked at the effects of desipramine and fluoxetine on FT and DM. The results of these experiments show that increasing the delay between pretest and test reduced FT during subsequent exposure (test). In addition, rats sensitized to and then withdrawn from either amphetamine or cocaine did not differ in FT or DM compared with control rats. Finally, both desipramine and fluoxetine reduced FT and increased DM. Furthermore, DM was consistently significantly negatively correlated with FT. These results support the use of an automated method for the evaluation of rat behavior in FST.

Effects of maternal stress during pregnancy on forced swimming test behavior of the offspring

It has been reported that gonadal steroids modulate brain and behavioral sex differentiation during development. Prenatal maternal restraint also alters development by affecting gonadal steroid levels in the fetus. Prenatal maternal restraint of animals decreases sex differences for sexual behavior, locomotion, aggression, etc. In recent work on animal models, we reported that, like humans, laboratory rats show sex differences in depression. From the present study, performed on Sprague-Dawley rats, we conclude that: 1) there are sex differences for depression in two different animal models (swimming-induced immobility and natatory tests); 2) there are also sex differences in open-field behavior; 3) prenatal maternal restraint decreases sex differences for depression but does not affect sex differences in open-field behavior; 4) prenatal maternal restraint affects female but not male behavior in the two depression tests used. These results suggest that: 1) sex differences reported in animal models of depression are under the control of gonadal steroids during prenatal brain development; 2) stress during early phases of development increases the risk for depression in adulthood.

P2B0118) - The effect of various agents affecting the GABAergic function on immobile behavior in forced swimming test.

P2B0118) - The effect of various agents affecting the GABAergic function on immobile behavior in forced swimming test.