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Benoit Petit-Demouliere. Franck Chenu.
Michel Bourin Forced swimming test in mice: a review of antidepressant activity Received: 11 June 2004 / Accepted: 21 September 2004 / Published online: 18 November 2004 forced swimming test (FST) remains one of the most used tools for screening antidepressants. Objective: This paper reviews some of the main aspects of the FST in mice. Most of the sensitivity and variability factors that were assessed summarized data found in the literature of antidepressant effects on the FST in mice. From this data set, we have extrapolated information on baseline levels of strain, and sensitivity against antidepressants.
shown that many parameters have to be considered in this test to gain good reliability. Moreover, there was afundamental inter-strain difference of response in the FST. Conclusions: The FST is a good screening tool withgood reliability and predictive validity. Strain is one of the Half a century ago, antidepressants were discovered by most important parameters to consider. Swiss and NMRI serendipity. In 1954, it was observed that some treatments mice can be used to discriminate the mechanisms of action for tuberculosis were exerting a beneficial effect in the of drugs. CD-1 seems to be the most useful strain for sense of well-being (Selikoff and Robitzek ; Bloch et screening purposes, but this needs to be confirmed with al. ). These results set iproniazid as the first some spontaneous locomotor activity studies.
antidepressant (Loomer et al. and the first memberof the monoamine oxidase inhibitor (MAO-I) family Keywords Forced swimming test. Depression. Mouse.
(Zeller and Barsky At the same time, imipramine was found to be effective in treating depression (Kuhn; Klerman and Cole ). At this point, a completely new approach was exposed: the monoamine theory ofdepression or biogenic amine hypothesis (Bunney and role of monoamines is not discussed here but it does not Antidepressants with an atypical activity fully describe the pathogenesis and aetiology of depres- sion (Heninger et al. Hyman and Nestler ;Nestler ; Nestler et al. Electronic Supplementary Material Supplementary material is In addition to clinical research, pre-clinical studies were necessary to test new drugs provided by pharmaceutical industry. Depression is defined clinically as a pathologicalcomplex of psychological, neuroendocrine and somatic B. Petit-Demouliere. F. Chenu. M. Bourin (*) EA 3256 "Neurobiologie de l'anxiété et de la dépression", symptoms that cannot be reproduced in animals and especially in mice. Only specific measurable behaviours (endophenotypes) can be assayed to be relevant in human depression (Holmes During this 50-year period, numerous animal models of depression have been designed, tested and assessed (Willner ; Lucki it is difficult to determine this validity in animal models of Mombereau The reserpine effects reversal test, depression (Geyer and Markou ; Willner and Mitchell designed by Costa et al. (), was the first attempt to screen imipramine-like drugs and led to the isolation of As semantic issues seem to exist between some authors desipramine and the demonstration of its antidepressant (Geyer and Markou Willner and Mitchell ), it is effect. To date, few models are commonly used for fundamental to have a clear definition of used terms. For screening antidepressant effects or studying the mechan- example, predictive validity and construct validity have isms of action of these molecules. The aim of this paper is not the same meaning for Willner and Mitchell than for mainly to review the characteristics of one of these Geyer and Markou. Predictive validity for Willner and models: the forced swimming test (FST) in mice, and to Mitchell is assessed by whether a model correctly discuss the main parameters that influence the sensitivity, identifies antidepressant treatments without making errors specificity and reliability of this model.
of omission or commission, and whether potency in the Porsolt et al. described "a new behavioural model correlates with clinical potency. For Geyer and method for inducing a depressed state in mice". The idea Markou, an animal model has predictive validity to the arose out of some learning experiments they were doing extent that it allows one to make predictions about with rats in a water maze. Most rats were finding the exit phenomena based on the performance of the model. The within 10 min but they noticed that other rats ceased narrow sense to refer to the ability of the model to identify struggling altogether and remained floating passively drugs with potential therapeutic value in humans appears (Porsolt et al. ). To describe this new behavioural limited for Geyer and Markou. It does not include the model in mice, the following procedure was adopted "1 h identification of any variables that influence both the after a single i.p. injection mice were dropped into the experimental preparation and the modelled phenomenon cylinder (height 25 cm, diameter 10 cm, 6 cm of water at in similar ways. This wider definition includes much of 21-23°C) and left for 6 min. Because little immobility is what Willner and Mitchell would discuss under the rubric observed during first 2 min, only that occurring during the "construct validity". Bearing in mind this opposition, last 4 min was counted. The duration of immobility predictive value in our paper will accord to the definition occurring in each minute was scored. A mouse was judged to be immobile when it ceased struggling and remained Construct validity does not represent the same concept floating motionless in the water making only movements for these authors. Geyer and Markou defined it as the necessary to keep its head above water" (Porsolt et al.
accuracy with which the test measures that which it is Male CD (Charles River) mice of 20-25 g, were intended to measure. For Willner and Mitchell, it is a housed ten to a cage with free access to food and water.
means of bringing the theoretical accounts of both the In the same paper, Porsolt tested a large range of disorder itself and the disordered behaviour exhibited by antidepressants and showed a reduction of immobility of the model into alignment. It includes neurobiological mice with all of them. The other usual clinical therapies mechanisms, aetiology or psychosocial mechanisms. We were also effective (e.g. electroconvulsive shock or will use this definition of construct validity that includes selective deprivation of REM sleep) (Porsolt et al. , etiological validity previously evocated (Geyer and The goal of the present paper is to summarize the Reliability refers to the consistency and stability with advantages and drawbacks of the FST in mice, as well as which the variables of interest are observed, and is the factors of variability of the test through an extensive relevant to both independent and dependant variables Willner used a third parameter to describe some animal models of depression: face validity (Willner ).
Face validity for an animal model of depression, represents the analogy between the model and the disease To evaluate the validity of an animal model, many criteria (i.e. how well they apparently resemble the human have to be explored. For example, we could consider depressive state). It refers to the phenomenological reliability and different types of validity: predictive, face, similarity between the behaviour exhibited by the animal construct, etiological, concurrent and discriminant. Un- model and the specific symptoms of the human condition.
doubtedly, the more types of validity a model satisfies, the This criterion is often criticized because of its non- greater is its value, utility and relevance to the human scientific aspect. It sums up specific patterns of depression condition. To establish the value of a model in basic and the model should not show features that are not seen neurobiological research, few of these parameters have to clinically. Although it appears to be useful to validate be satisfied (Geyer and Markou It was argued that models, such a criterion is actually not necessary (Geyer there are only two criteria that a model must satisfy to and Markou Because the pharmacotherapy of establish its value in basic neurobiological research: depression typically requires chronic drug treatment to reliability and predictive validity. Nevertheless, the pro- obtain a full response, face validity (Willner takes cess of construct validation is valuable in further devel- account of the necessity, or not, to use chronic adminis- opment and refinement of the model; however, in practice tration to have an antidepressant effect and the specificity of observed features. Irrespective to how it responds to 24 days were effective at 10 mg/kg per day and 18 mg/kg acute antidepressant treatment, to have face validity, an per day administered in drinking water. This delay of animal model if depression must respond to chronic action provides further data to increase the face validity of FST in mice, even if their experimental paradigm was not These types of validity are discussed below for the FST.
the original method for the FST. (Dulawa et al. For other types of validity, the FST was estimated to have Moreover, we have to consider that some authors using a lack of convergent validity and a possible etiological standard methods showed that fluoxetine was effective acutely at 16 mg/kg in the FST with CD mice (Da-Rochaet al. This shows the preponderant place ofmethodological parameters in behavioural studies (e.g.
In addition, from an ethical point of view, this animal The FST is currently a popular model, due to the low cost experiment requires only a single exposure to the stressful of the experiments and because it is arguably the most stimulus (Thierry et al. ). The used dose in the test as reliable model available (Holmes Moreover, it has well as in other tests in mice are high doses compared to been reported to be reliable across laboratories (Borsini human but the pharmacokinetic parameters in mice are very different (i.e. half-life is about 1 h for mice comparedto several hours in human). Face validity for the FST withmice is not strong; chronic administration remains to be fully studied in order to increase this face validity.
To evaluate predictive validity, correlating potenciesbetween a model and the condition it models is possible (Willner In a comparative review of drug effects onimmobility time in mice, Borsini and Meli adopted a limit The construct validity of the FST is difficult to establish of 20% reduction of immobility to consider an antide- and questionable. Indeed, the onset of immobility pressant effective on the test. They show that 94% of observed during the test is hard to interpret. Porsolt et antidepressants decrease the immobility time in mice al. () described this state as a behavioural despair (Borsini and Meli In this study, they found that "reflecting a state of lowered mood". He had also 83% of classes of drugs decrease immobility time in the dissociated hypothermia induced by forced swimming mouse. This lack of specificity may be largely explained from immobility occurring in these conditions and also by methodological considerations. Some authors changed from drug-induced hypothermia in rats (Porsolt et al.
the scoring method, other authors recorded animal move- ). The anthropomorphic interpretation was assessed ments by using automated devices. Moreover, false and replaced by other assumptions: a shift from active positive effect of motor activity enhancing drugs would coping to passivity, a means to conserve energy (Arai et al.
have been detected with an actimeter, where psychostim- ulant drugs could reduce immobility without antidepres- "entrapment" described in clinical situations (Cryan and sant effect (Porsolt et al. Nevertheless, the FST is a Mombereau ). This passive behaviour could also be suitable model to detect antidepressants due to the fact that considered as unwillingness to maintain effort in this it detects the majority of antidepressants and discriminates inescapable situation. Immobility may be seen as an antidepressants from neuroleptics and anxiolytics (Borsini adaptative response to an inescapable situation. This strategy could be perceived as a successful coping rather Together, these data provide us with a broad spectrum of antidepressant effects with good reliability and some Immobility observed in the swim test seems not to be answers to the lack of specificity of the test, which has related to behaviour in the tests used in anxiety models been discussed (Schechter and Chance ).
(elevated-plus maze, hole-board test, locomotor activity)(Hilakivi et al. ). Even if the onset of immobilityremains hard to interpret, the aetiological part of construct validity could be highly relevant. The stress leading to thebehavioural despair may be involved in the aetiology of A second characteristic of the FST is that acute drug some types of depression in humans (Geyer and Markou treatments are effective in this model and do not ). Nevertheless, the FST has a very little construct correspond to the clinical time course of their action.
validity due to this acute and non-ecologically relevant One of the main arguments increasing the face validity is stressor that produces this behaviour (Willner and Mitchell that chronic treatments reinforce the effects of antidepres- sants on immobility. It showed several differences between To summarize, FST has strong predictive validity, good chronic and subchronic treatment of a SSRI, fluoxetine, in reliability, some face validity and poor construct validity.
the FST with BALB/c mice weighting 25-35 g (Dulawa et In a review of the causes of immobility in the FST, West al. ). Four days of treatment were ineffective, whereas ) concluded that FST "no longer appears to be a valid model of depression. Nonetheless the forced swim factor that could potentially be used in the treatment of test is still likely to be useful in understanding anti- depression. They used the FST and showed that brain- depressants treatments". This point of view should be derived neurotrophic factor (BDNF) infusion in the ventral moderated by a consideration on "what is a valid model of tegmenta area resulted in 57% shorter latency to immo- bility relative to control animals, in the FST in rats (Eisch When pre-clinical tests were created to study the et al. ). This use of the FST had already been depressive state, the first role for models of depression described previously with a 70% decrease in the immo- was to predict antidepressant potency. Moreover, the bility time compared to vehicle-infused controls after validity of these tests was largely based on an empirical BDNF infusion (Siuciak et al. ). Other ways of observation, namely that the two major groups of investigation for depression use the FST as model of antidepressants, MAO-I and tricyclic drugs (TCAs), are depression. Acute antidepressant treatment attenuates swim stress-induced corticosterone release in the rat The FST, as described by Porsolt et al. (), has been (Baez and Volosin ). NK2-receptor antagonists, K+ designed to be "a primary screening test for antidepres- channel openers and K+ channel blockers were considered sants". For this purpose, FST is a good model for for their antidepressant-like properties in the forced swim screening antidepressants, maybe the best one. FST test (Guo et al. ; Redrobe et al. ; Slattery et al.
shows a strong sensitivity to monoamine alterations, but ). Nitric oxide synthase (NOS) or neurosteroids have it should not be forgotten that other antidepressants been tested in the FST with mice to look for an treatments, such electroconvulsive shock, are efficient antidepressant-like effect (Harkin et al. Khisti et (Porsolt et al. ). To summarize these ideas, we can al. Many studies keep using the FST, not only for consider that "The FST models a very specific cluster of screening for antidepressant effects, but for a more stress-induced behaviours that have no direct, empirical neuropsychological purpose. This utilization of the FST relation to depression symptoms in humans, but which are differ from the monoaminergic purpose it is often used.
nonetheless exquisitely sensitive to monoaminergic ma- Nevertheless, this model of depression is not only linked nipulations" (Holmes Additional possibilities for to monoamine. The uncontrollable stress involved during the FST should be considered on a more neuropharmaco- the test may implicate many mechanisms of reaction that logical point of view. This test also provides a useful could be considered as possible investigation ways. The model to study neurobiological and genetic mechanisms fact that electroconvulsive seizures are effective in the test underlying stress and antidepressant responses (Porsolt argues for its ability to pick up broader mechanisms of action (Nestler et al. The relevance of using the Moreover, new approaches of research for antidepres- FST for this new ways of research needs clinical sant treatments continue to use the FST as a preliminary correlations to validate also the FST for this utilization.
test. For example, some authors work on neurotrophic The development of clinically effective antidepressant Table 1 Summary of some modifications tested on the FST in mice Bourin et al. (1998a); David et al. (2001a) Alonso et al. (1991); David et al. (2001b); Voikar et al. (2001) Hilakivi et al. (1989); Yates et al. (1991) Lucki et al. (2001); Voikar et al. (2001); Bai et al. (2001); David et al. (2003) Arai et al. (2000); Taltavull et al. (2003) drugs with novel mechanisms should give answers to this parameter provide a way to distinguish the antidepressant drugs from caffeine, anticholinergics, and antihistaminics, Another point is the utilization of the FST for which gave a false positive response in 10 cm diameter genetically modified animals that is applicable to study cylinders. The selective effect of antidepressants, namely, mechanisms of action of antidepressant on the test. For the rotatory locomotor activity during swimming can also example, the decrease of immobility observed after be studied (Sunal et al. In our laboratory, we use a paroxetine administration in wild-type mice is absent in cylinder with the closest available diameter to the original 5-HT1B knockout in the test (Gardier et al. ). Other test's diameter, associated with a check of variation of data with knock-out mice can be useful to determine the locomotor activity that can discriminate false-positive role of NA or 5-HT in the test; for example with mice lacking serotonin transporter (Holmes et al. ordopamine-beta-hydroxylase deficient mice (Cryan et al.
Depth of water This parameter had to be considered as This new employment of the test permits to better mice should not sense a limit under the level of water.
know the mechanisms of action of drugs on the FST Their tails should not touch the bottom of the cylinder or involving or not the monoamine, i.e. for new possible the behaviour of the mice would be altered. Increased therapies for example, BDNF+/- mice (MacQueen et al.
depth of water decreases the time spent immobile. No or inducible BNDF knock-out (Monteggia et al.
paper clearly described this process in mice; this parameter was shown to alter the behaviour of the rat (Borsini andMeli Detke and Lucki The originaldescription of the FST by Porsolt et al. () explains that 6 cm of water is sufficient. But mice can sense thebottom of the cylinder with this level of water. In our There have been many modifications of the FST but laboratory, the water level is at least 10 cm. Some improvements of the test are often poorly validated modifications of Porsolt's paradigm have often been used; (Bourin et al. ). Many parameters have been assessed one of the most quoted is the method of Aley and Kulkarni in order to increase the sensitivity, specificity and ). They measure immobility in a glass jar (21×12 reliability of detection of antidepressant activity. The cm) containing 12 cm of water maintained at 22±1°C, following list describes some of these modifications of during a 6-min period. It is important to consider that the FST (Table The two columns of Table separate each only main modification of the original test is the increased modification between variability and sensitivity. A "vari- depth of water. This procedure is consistent with the one ability factor" is assessed to check what parameter could we use and should be considered as the actual standard increase or decrease reliability of the test between different Interval of observation/scoring Porsolt's paradigm hasbeen modified by some researchers in order to increase the sensitivity or the specificity of the FST. Some authors havecreated a totally new analysis procedure for scoring Automated device/water waves Different procedures have immobility. The observation interval can be separated into been elaborated to automate the FST. Video-tracking, 5-s parts in which the main behaviour is scored (Lucki computer analysis or wave analysis were used to score the ). Analysis of the behaviour of the mice can be totally immobility of rodents. From the data set, one can extract different with categorization of a specific behaviour full or partial turns, clockwise or counter-clockwise (Schramm et al. Some authors made a series of rotations, total activity, and speed of swimming clockwise observations at 30 s. intervals and the mouse was rated as and counter-clockwise (Denenberg et al. Another immobile (score 0) or not (score 1) for each observation author used an apparatus consisting of a transparent plastic cylinder (10×20 cm) containing 7 cm of water (23°C).
Movement by the animal created a waveform in the water, Time between treatment and FST This factor is not often resulting in a converted digital signal (Browne ). The considered but may explain some of the differences ease of use of these systems appears not to counterbalance between FST results. Two possibilities seem to be the cost of the equipment. Few studies use an automated available: acute injection 1 h before the FST as described video-tracking device, and mainly as a confirmation tool by Porsolt et al. or acute injection then the FST (Eisch et al. Nevertheless, some automated devices when the maximal effect is intended. This requires a time- employed in FST studies were reported to be reliable for antidepressant screening (Yoshikawa et al. Water temperature The influence of water temperature on Cylinder diameter To test this parameter, mice were forced immobility time of the mice was studied. An effect of to swim for 15 min in tanks of 10 (the original diameter of water temperature was revealed; a higher temperature the Porsolt's forced swimming chamber), 20, 30, and 50 (35°C) resulted in shorter immobility time after 10 min of cm diameter in 20 cm deep water. Modifications of this forced swimming (Arai et al. Other data suggest that immobility, which develops rapidly during forced Environment of the laboratory Interactions with laboratory swimming in cold water, may result from dramatic environment have been studied in several strains of mice inhibition of neural functions because of severe brain on few behavioural tests (open field, elevated plus maze, hypothermia (Taltavull et al. Currently, most water maze, alcohol preference) (Crabbe et al. studies use warmer water between 23°C and 28°C. In Despite standardization, there were systematic differences our laboratory, we choose a temperature between 23°C and in behaviour across three different laboratories. In our opinion, FST is less sensitive to variation of laboratoryenvironment (noise, air temperature, light, atmosphere Wheel water tank Some authors have tried to measure immobility time in another way. A wheel was immersed inthe water tank. Mice placed on this apparatus keep turning Food restriction Food restriction can strongly modify the wheel vigorously; when they abandon their attempts to behavioural responses, as shown with amphetamine or the escape from the water, the wheel stops turning. The FST. The authors used FST for two sessions with two number of rotations of the water wheel is counted. All groups of DBA/2 mice. One group was isolated and food antidepressants tested increased the number of rotations as restricted, the other group was isolated but had free access tranquillizers, anticholinergics and antihistaminics were to food. Immobility time was significantly decreased in the not effective. It was suggested that this water wheel test food-restricted group compared to the other group (Cabib was more appropriate as screening test for antidepressants than Porsolt's test with regard to both objectivity andspecificity (Nomura et al. ).
Gender Differences of sensitivity between male andfemale mice were revealed by some studies dependingon the strain used. David et al. ) described a different sensitivity to antidepressants in the FST related togender. Imipramine and paroxetine were active on CD1 Acute versus chronic administration The effectiveness of male and female but at different doses. Another study acute treatment is a particularity of the FST. Useful for a showed a difference between male and female mice but screening test, it appears to decrease the face validity of only in some strains; FVB females, for example, had a this model, as the clinical time course requires chronic shorter floating time than males (Voikar et al. administration to be active. Experiments were made to Sexual differences have also been described in another find out the effects of chronic administration on the FST.
study of immobility, which was higher in males than in Subchronic or acute effects were increased by chronic Housing of animals/isolation of animals All studies have Age of the mice This parameter should be considered in shown that housing was a critical parameter. In the above parallel with weight. Our team has already shown a strong mentioned study of Cabib (see food restriction section), a difference between younger and older mice groups.
group of DBA/2 mice was isolated for 13 days and Sensitivity to some antidepressants is profoundly altered.
compared with group-housed mice in the FST. They Tricyclic, noradrenaline reuptake inhibitors (NRI) and showed a significant increase of the immobility time in the serotonin reuptake inhibitors were more active in 4-week- isolated group (Cabib et al. Yates et al. old mice than 40-week-old Swiss mice (Bourin et al. linked this difference with the age of the mice. After David et al. In our laboratory experiments, we having isolated mice for 24 h prior to a 15-min FST, they showed an increase in immobility time in 17- to 21-day-old Swiss Webster mice but not in 26- to 30-day-old mice.
Circadian rhythm An effect of circadian rhythm was In another study, the immobility time in the FST was shown in response to antidepressants in the FST. FST was shortened in NIH Swiss mice isolated for 2 or 5 days, carried with three strains of mice: C3H, C57BL/6J and suggesting an improved ability to cope with stressful ND/4. Immobility time was scored at noon (1200-1400 situations (Hilakivi et al. Yates et al. Isolation hours) and midnight (0000-0200 hours). For C3H/Hen seems to have strain-dependent effects on the FST, but mice, duration of immobility was greater at midnight none of these studies had the same isolation time. If (Dubocovich et al. Another study did not show any isolated for a longer period (8 weeks), mice displayed difference between the FST made at noon (1100-1200 lower levels of immobility time when exposed to this test hours), early dark (2000-2100 hours) and at midnight (Karolewicz and Paul ). Nevertheless, isolation, e.g.
(0100-0200 hours) for BALB/c and C57BL/6J mice for surgery, had to be specified in methods of a paper, as it (Raghavendra et al. ). Genetics studies on the Clock may modify dramatically immobility time of the FST.
gene, implicated in circadian rhythm, revealed an effect ofthis parameter on immobility time (Easton et al. Observer The most important source of variability (and the Studies in our laboratory are only made between 0800 and best way to consider in order to increase the sensitivity of 1200 hours to avoid any risk of behavioural modification the FST), with identical environmental parameters, is the observation. Like all behavioural studies, the observer is the main actor of the test and reproducibility between second session. This second session has been assessed for laboratories is a matter that affects all these tests. The the construct validity of the FST. Memory process was scoring of the immobility time should be strongly involved to explain immobility of the rat. The absence of considered and assessed by all teams. The mouse is second session with mice removes this problem and judged to be immobile when it makes only movements simplifies the test. In their experiments, Alcaro et al.
necessary to keep its head above water. It can move in the ) evaluated behavioural responses to FST in naive cylinder but without struggling movements. The analysis animals and in animals pre-exposed to the FST 14 days of active behaviours in the FST has strengthened the before the test session. They showed a major effect of the possibility of replicating the experiments.
pre-session FST in mice on immobility time with adramatic increase after pre-exposure. For Andreatini and Side preference in rotation A study was made on side Bacellar (), "this test showed a very low intra-class rotational preference of mice during the FST. Krahe et al.
correlation coefficient in the test-retest design, which concluded that side preferences of spontaneous suggests a poor reliability of these measures". These rotational behaviour may account for inter-individual results suggest that the behavioural parameters of the behavioural despair are not stable. Therefore, they arepossibly more related to state than trait characteristics, this Strains Strain is one of the most important parameters to test is not appropriate to evaluate trait characteristics deal with (Lucki et al. ). Important differences exist which are supposed to be stable over time without between strains in both immobility observed and effects of treatment. Some authors use the test/retest paradigm to imipramine (Porsolt et al. ). Genetic background avoid variations and to maintain consistency in the could modify response by providing an inappropriate immobility time between different groups (Hirani et al.
baseline level of behaviour (Holmes There is a maximal tenfold difference in baseline immobility scoresin control animals between strains and baseline level doesnot correlate with antidepressant sensitivity (Lucki et al.
Several gender dissociations suggest the strain andtask specificity (Voikar et al. Intra-strain and inter- Many antidepressants have been tested with the FST on strain comparisons indicate that the biological substrates mice. Some results available for all classes of antidepres- mediating performance in the FST and the tail suspension sants with different strains of mice are reviewed here.
test (TST) are not identical. For example, in NIH-Swiss In the literature, the lowest control immobility time was mice, a 7-fold difference in baseline immobility was obtained with FVB/NJ (13 s) mice and highest with ddY observed between the FST and TST. By contrast, the baseline immobility in C57BL/6 mice was similar in both Table summarises the results for three inbred strains procedures (Bai et al. ). There is a continuum of and four outbred strains that are compared over their variation in basal responses from almost no time spent results in the FST. A more detailed version of this table, immobile by DBA/2J mice to more than 210 s of with more antidepressants and strains, is available as immobility in a 360-s test session with Balb/cJ mice Electronic Supplementary Material (ESM).
(O'Neil and Moore In one of our studies, we have Inbred strains have been found very defective in the shown that drug sensitivity is genotype dependent. FST FST with antidepressants. Only one type of antidepressant results have shown that Swiss mice were the most (DRI), bupropion, was significantly effective in the FST sensitive strain to detect serotonin (5-HT) and/or norad- with C57BL/6Rj. For C57BL6j and DBA/2, no positive renaline (NA) treatment. The use of DBA/2 inbred mice result coupled with a locomotor test was found in papers may be limited, as an absence of antidepressant-like we analysed. Outbred strains of mice are more responsive response was observed in the FST (David et al. to antidepressants in the FST than inbred strains. These Control mice from the same breeders with comparable four outbred strains may be used for at least three classes housing conditions should have the same immobility time of treatments. The most frequently used strains, CD1, in all laboratories. However, a gene-environment interac- NMRI and Swiss, have positive results with most of the tion is possible and may account for some difference antidepressants in the FST. HaM/ICR seems to be very between laboratories (Wahlsten et al. ). For example, responsive to drugs in the FST but it is a rare strain. Only in our data set, animals of the same strain that received no one paper was found to use this strain on the FST (De treatments do not have the same immobility time (for CD- Graaf et al. There are many differences between 1 from 135 s to 223 s of immobility time).
strains; DBA/2, for example, does not have an appropriateresponse to the FST. This strain should not be used for Test/retest This method is used normally for rats. In a first behavioural studies with the FST. CD-1 is not useful to session, the animal is able to discover the test, rat usually discriminate different mechanisms of action in the test. It explore the water surface and dive. In a second session could be used as a screening model but, to recommend this were they will be scored, rats are familiarized to the test strain, we need to know if Dopamine Reuptake Inhibitors and do not try to dive. Mice do not have this behaviour (DRI, e.g. bupropion), NRI and MAO-I are effective in the and this explain the easy use of mice that do not need a Table 2 Antidepressant effects on the FST with different strains of relation to depression symptoms in humans" (Holmes ). Care must be taken on the strain used for the test and all the experimental parameters involved. For ascreening test, CD-1 can be a good strain to use to find out if a treatment has an antidepressant-like activity.
Despite their intrinsic limitations, the full potential of animal models of depression has not yet been realized and they represent an under-explored opportunity for drug development. Such opportunities arise from the molecular dissection of the biological features of the models (Wongand Licinio ).
*, treatment is effective and locomotor activity was tested without Anjaneyulu et al. Biziere et al. (Biziere et +, treatment is effective but locomotor activity was not tested −, treatment has no potency and does not increase locomotor activity al. Bourin et al. (), Bourin et al. Different categories of drugs are listed in the first column. For Clenet et al. Cryan et al. (Devoize et al.
example, DRI includes bupropion, nomifensine or amineptine.
), Devoize et al. Eschalier et al. (), Kato Atypical antidepressants include mianserin, iprindole and others. A positive result, represented by a star, signifies that at least one studyshowed a significant effect of one drug of the considered category.
Miura et al. Mogilnicka et al. Redrobe et For a more detailed table, Electronic Supplementary Material is al. (), Rogoz et al. (), Scotto di Tella and Mercier available with all drugs and effects reported in different studies ), Stenger et al. (), Szymczyk and Zebrowska-Lupina Zocchi et al. ).
FST with CD-1 without increasing spontaneous locomotoractivity of the animals.
Even with a very precise binding of antidepressants, it is often difficult to understand the mechanisms of action ofantidepressants. Some of our previous works showed that Alcaro A, Cabib S, Ventura R, Puglisi-Allegra S (2002) Genotype- dopaminergic activity compounds are not easy to be active and experience-dependent susceptibility to depressive-likeresponses in the forced-swimming test. Psychopharmacology on the FST. On the other hand, the binding or the drug activity at the synaptic level is only an indirect under- Aley KO, Kulkarni SK (1989) GABA-mediated modification of standing of the activity of drug in a whole animal. It was despair behavior in mice. Naunyn Schmiedebergs Arch Phar- showed in our lab (David et al. ) as well as in Lucki's Alonso SJ, Castellano MA, Afonso D, Rodriguez M (1991) Sex laboratory that depending on the strain, the effect size is differences in behavioral despair: relationships between beha- quite different (from 0% effect for desipramine in C3H/ vioral despair and open field activity. Physiol Behav 49:69-72 HeJ to almost 60% of decrease of immobility time with Andreatini R, Bacellar LF (2000) Animal models: trait or state measure? The test-retest reliability of the elevated plus-maze FST was designed by Porsolt as a primary screening test and behavioral despair. Prog Neuropsychopharmacol BiolPsychiatry 24:549-560 for antidepressants. It is still one of the best models for this Anjaneyulu M, Chopra K, Kaur I (2003) Antidepressant activity of procedure. This is a low-cost, fast and reliable model to quercetin, a bioflavonoid, in streptozotocin-induced diabetic test potential antidepressant treatments with a strong predictive validity. However, the low face and construct Arai I, Tsuyuki Y, Shiomoto H, Satoh M, Otomo S (2000) Decreased body temperature dependent appearance of beha- validities should not forbid the use of this model for vioral despair in the forced swimming test in mice. Pharmacol neurophysiological studies. It has a great sensitivity with all the antidepressant classes and all the mechanisms of Baez M, Volosin M (1994) Corticosterone influences forced swim- action of treatments could be determined, but clinical induced immobility. Pharmacol Biochem Behav 49:729-736 Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and correlations should be considered very carefully. Studying interstrain differences in models of "behavioral despair".
the method of action of an antidepressant is different from studying aetiology and how to cure depression.
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