Update in the methodology of the chronic stress paradigm: internal control matters
© Strekalova et al; licensee BioMed Central Ltd. 2011
Received: 18 July 2010
Accepted: 27 April 2011
Published: 27 April 2011
To date, the reliability of induction of a depressive-like state using chronic stress models is confronted by many methodological limitations. We believe that the modifications to the stress paradigm in mice proposed herein allow some of these limitations to be overcome. Here, we discuss a variant of the standard stress paradigm, which results in anhedonia. This anhedonic state was defined by a decrease in sucrose preference that was not exhibited by all animals. As such, we propose the use of non-anhedonic, stressed mice as an internal control in experimental mouse models of depression. The application of an internal control for the effects of stress, along with optimized behavioural testing, can enable the analysis of biological correlates of stress-induced anhedonia versus the consequences of stress alone in a chronic-stress depression model. This is illustrated, for instance, by distinct physiological and molecular profiles in anhedonic and non-anhedonic groups subjected to stress. These results argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype during experimental paradigms of depression as an internal control, for more refined modeling of this disorder in animals.
Keywordsanimal model of depression chronic stress sucrose test anhedonia antidepressant treatment gene expression profiling neuroinflammation mouse
Depression is projected to become the second most common cause of disability worldwide by 2015. Depression as a major health issue is illustrated by its death-toll, which currently claims more lives per year than road-traffic accidents [1–4]. At the same time, there is an obvious need for an improvement in the treatment of depression, as up to 45% of depressed patients do not show improved mood after advanced therapy and 15% of patients do not respond to any antidepressant therapies . The Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) defines depression by the presence of at least one of two core symptoms: anhedonia; a decreased ability to experience pleasures, and depressive mood; lasting minimally 2 weeks [6, 7]. Since anhedonia, on the one hand, is a cardinal phenomenon of depressive disorders, and on the other, can be evoked in rodents, the hedonic deficit might be considered as a primary feature to be addressed in pre-clinical models of depression. Coping and cognitive deficits, low exploratory motivation, circadian and sleep disturbances, aggressive and anxiety traits, decreased sexual and increased submissive behaviour, social avoidance, deterioration of the coat state and other changes, which can be evoked in animals, with some considerations  are regarded as parallels of subsidiary depressive symptoms [9, 10].
The aim of this review is to analyze the major methodological drawbacks in mouse models of depression with a focus on its principal feature, anhedonia, in a chronic stress paradigm, and to share with the reader several procedural modifications resulting from our own experiences with a chronic stress model in C57BL/6N mice. We believe that the changes to methodology proposed here provide important advances in modelling the neurobiological basis of depression in rodents and that their implication can help develop more effective therapeutic strategies.
Challenges in modelling depression and anhedonia using chronic stress paradigms
The chronic stress paradigm is considered to have a greater aetiological relevance and face validity in mimicking depression than other animal models, and therefore has become one of the most broadly used pre-clinical paradigms of this disorder [11–14]. The first experiments using this model were undertaken by Katz and colleagues in rats, and involved rotating stressors applied over 21-days . These procedures were later modified by Willner resulting in higher length of experiment and lower severity of stressor . These experiments resulted in a decreased preference for, and intake of palatable solutions such as sucrose or saccharine. This was defined as stress-induced anhedonia. This anhedonic state was accompanied by an increase in the thresholds required for intracranial self-stimulation and was reversed by anti-depressants, but not by neuroleptics or anxiolytics [13, 17]. By now, a number of variants of chronic stress procedures had been proposed in both rats and mice and had been shown to evoke, in addition to anhedonia, the subsidiary depressive-like features mentioned above [18–31].
Regrettably, a number of studies revealed inconsistencies in the induction of hedonic deficit in chronic stress models in both rats and mice [32–35]. For example, in one study, Wistar and PVG hooded rats were subjected to chronic mild stress; stressed animals of both lines showed "unreliable" decreases in sucrose intake, which were "inconsistent" over time. None of stressed animals showed a decrease in the intracranial self-stimulation, evaluated by 50% of maximal response rate in the rate/frequency function . Problems with reproducibility could also be due partly to the limited accuracy of the sucrose test, which, in its current state, does not have sufficient resolution to discriminate between anhedonic and non-anhedonic individuals within a stressed population [37–39]. In addition, some of multi-disciplinary studies, using anhedonic chronic stress models of depression, have resulted in abstruse and contradictory outcomes, and failed to define a consistent molecular, neuroanatomical and physiological phenotype in either rats or mice. Data on their locomotion, anxiety, exploration, and other behaviours often demonstrated paradoxical and conflicting behavioural changes; many of them showed discrepancies between the behavioural phenotype of chronically stressed animals and human symptoms of depression. Together, controversies with reproducibility of stress-induced anhedonia, defined by sucrose preference data and identification of biological correlates of depression greatly limit the value of this method to model pre-clinical depression .
Apart from methodological problems, application of the chronic stress approach has encountered some conceptual drawbacks. The most obvious is that in previously proposed models, all effects observed in groups of chronically stressed animals with signs of a decreased sensitivity to reward, are attributed to an hedonic deficit. It is important to note that stress alone can evoke a number of physiological alterations, which are not associated with a depressive-like behavior and anhedonia. With the originally proposed models and their analogues it was not possible to correlate findings obtained in chronically stressed animals with anhedonia, thus, specific biological correlates of hedonic deficit could not be addressed.
Studies with our new model of stress-induced anhedonia suggest that unresolved methodological difficulties in measuring behaviour in chronically stressed animals may be the origin of the above problems. Here, we present data obtained across several experiments, which reveal the major sources of behavioural artifacts in chronic stress mouse models of depression. These data enable us to propose several changes to the accepted methodology which are validated by both behavioural and molecular correlates of anhedonia.
Anhedonia is exhibited by a subgroup of animals in chronic stress paradigms
Partial depressive-like outcomes in chronic stress models of depression
Measure of a depressive-like state
Low sucrose preference
5-week social stress
Increase of CORT, Low sucrose preference
Low sucrose intake
10-day social defeat
Social avoidance, Low sucrose preference
7-week unpredictable CMS
Eleven common mouse strains
Coat deterioration, Low sucrose preference
Vary in different strains
The inter-individual variability in susceptibility or resilience to stress-induced decreases in sucrose preference observed in these, and our, paradigms suggest that this phenomenon is typical, even for inbred lines of animals [21, 56, 59–63]. A variety of potential mechanisms may underlie this phenomenon: 1) pre-natal and early environmental factors  epigenetic mechanisms consisting in DNA and chromatin modifications, histone acetylation and methylation [65, 66] and switches and error-prone DNA replicates ; 3) large-scale organization of gene expression levels and multigenic trait mechanisms [68, 69], 7) posttranslational regulation of proteins . Generally, preservation, even in genetically homogenious lines of animals, of inter-individual variability of physiological parameters allows one to develop hypotheses regarding its importance as a biological factor of adaptation and survival, especially relevant in a stressful environment, which may be mediated by specific biological mechanisms.
Physiological features of stress and stress-induced anhedonia in mice
Physiological correlates of stress and stress-induced anhedonia in our model
Anhedonic Changes vs. control
Non-anhedonic Changes vs. control
1. Floating in forced swim test
2. Immobilization in tailsuspension test
3. Novelty exploration
4. Burrowing behaviour
5. Contextual memory in passive avoidance
6. Contextual fear conditioning
[Tokarski et al. Impaired hippocampal plasticity in mice with hedonic deficit, induced by chronic stress (unpublished)]
7. LTP in the CA1 area of the hippocampus
[Tokarski et al. Impaired hippocampal plasticity in mice with hedonic deficit, induced by chronic stress (unpublished)]
8. REM sleep
9. Home cage activity during dark phase
10. Anxiety-like behavior in O-maze and dark-light box
11. Open field locomotion under modest lighting
12. Aggressive behavior
[, unpublished data]
13. Auditory fear conditioning
[Tokarski et al. Impaired hippocampal plasticity in mice with hedonic deficit, induced by chronic stress (unpublished]
14. Body weight
As well as behavioural changes, we found specific physiological abnormalities in anhedonic animals; a lack of ex-vivo LTP induction capacity in the CA1 area of the hippocampus during high frequency stimulation protocols, elevated duration of REM sleep and home cage hyperlocomotion (Table 2). Chronic treatment with an SSRI precluded stress-induced disruption of LTP induction in hippocampal slices. This data correlates with human studies showing that impaired hippocampal function and synaptic plasticity are sensitive to antidepressant treatment [73, 74]. The augmentation of REM sleep and disturbances in diurnal rhythms observed in clinical studies and animal models of depression are thought to be characteristic of clinical depression [3–7, 18, 20]. In particular, depressed patients exhibit a high percentage of REM sleep when compared to other neuropsychiatric disorders with shared pathophysiology.
At the same time, many changes in animals were found to occur in stressed animals irrespectively of the presence of hedonic deficit: hyperlocomotion observed in brightly illuminated open field, hypoactivity in the dark open field, increased scores of anxiety-like behaviour in the dark/light and elevated O-maze tests, high scores of aggressive behaviour and loss of body weight (Table 2). Increased scores of anxiety, aggressive behaviour, locomotor inhibition and behavioural invigoration are also well documented in humans and are thought to be the result of stressful experiences [3–7, 28, 31, 75].
In the present model, stress-induced loss of body weight, high scores of anxiety and locomotor diturbances are comparable in anhedonic and non-anhedonic mice that might be regarded as an indication of similar impact of the stress in these animals. Data concerning anxiogenic-like changes in the O-maze in C57BL/6J mice with and without social avoidance and anhedonia evoked by social defeat stress  are in line with our findings. In this study, no difference in body weight between two groups was observed at the time point of experiment, when signs of elevated depressive- and anxiety-like behaviour were revealed in stressed animals. The CD1 mice, either resilient or susceptible to chronic social stress, as measured by changes of basal CORT levels and sucrose preference, showed no alterations in body weight . In studies on other mouse lines, a manifestation of stress-induced depressive-like features correlated with a loss of body mass [13, 23, 41, 60]. This suggests that species-specific differences across different strains of laboratory mice may underlie a distinct relationship between anhedonia and body weight. In line with our results, both anhedonic and non-anhdonic Wistar rats in the chronic stress model were found to have similarly decreased body weight . We believe that the absence of differences in body mass in our model between anhedonic and non-anhedonic mice may be caused by the 'ceiling effect' of stress on physical parameters in a specific strain. Similar values of body weight in subgroups of stressed mice can be an important factor, which prevents significant confounds in the behavioural comparison of anhedonic and non-anhedonic mice. Should body weight vary between these groups, their comparison in behavioural tests based, for example, on the measurement of liquid intake and foot shock application is likely to be compromised by distinct metabolic features and a response to an electrical stimulation.
The latest literature suggests a link between common inflammatory factors, loss of body weight and sickness behaviour - a state which is related to anhedonia. In the light of recent identification of inflammatory factors, which underlie both sickness behaviour and depression , it can be speculated that stress-induced decreases in body weight, in addition to classical mechanisms of hormonal secretion and sympathetic activation, might be mediated by activated inflammatory pathways involved in the pathogenesis of anhedonia. Of note, in our model stressed, anhedonic mice showed disrupted burrowing behaviour that we believe to be related to both lesions of the dorsal hippocampus and sickness behaviour [38, 39, 77]. While, in our studies, both susceptible and resilient animals showed a robust decrease in body weight, a potential contribution of inflammatory factors to this consequence of stress could be an interesting question to be addressed experimentally.
Features of resilience and susceptibility to stress-induced depressive state in animal models
Not changed 
Not changed 
Not changed 
Coat state and self-grooming
Not changed 
Not changed 
Not changed 
Not changed 
Conditioned place preference
Not changed 
Identification of molecular correlates of stress and stress-induced anhedonia
Comparison of gene expression in anhedonic and resilient stressed mice versus non-stressed controls
# Genes Up
# Genes Down
# Genes Up
# Genes Down
Cellular Assembly and Organization
transport of vesicles
biogenesis of cytoskeleton
morphogenesis of neurites
formation of vesicles
formation of filaments
formation of neurites
psychological process of mice
exploratory behavior of mice
movement of brain cells
migration of brain cells
Nervous System Development and Function
development of neurites
development of axons
long term depression
prepulse inhibition of mice
coordination of mice
spatial memory of mice
neurodegeneration of neurons
Effects of COX-2 inhibitor in mice subjected to chronic stress
Changes versus non-stressed control
Stressed drug naive
Stressed treated with COX-2 blocker
Contextual fear conditioning
Parameters of anxiety in elevated O-maze
Percentage of anhedonic mice
Together, our data suggest distinct molecular correlates of states of stress and stress-induced anhedonia in a proposed model. Similarly, studies in a social defeat paradigm in C57BL/6J mice demonstrated that susceptible and resilient individuals, which are distinct in scores of social avoidance and sucrose intake and preference, have differential levels of immediate early genes Arc and Zif268 in the frontal cortex, BDNF in the hippocampus and the ventral tegmental area and DeltaFosB in the nucleus accumbens [21, 50–53]. Studies in Wistar rats showed distinct expression patterns of BDNF and vascular endothelial factor in the hippocampus . Differential expression of AMPA receptors in the dorsal hippocampus was revealed between resilient and susceptible individuals in a social stress model in outbred mice . Further studies are required to address key pathogenetic gene expression factors of resilience and susceptibility to a depressive syndrome precipitated by stress; such studies are under way.
Limitations of the sucrose preference test in assessing anhedonia in chronic stress paradigms
Several behavioural paradigms are currently used to measure sensitivity to reward in rodent chronic stress models. These include consumption of palatable solutions, progressive ratio responding, intracranial self-stimulation, novel-object place conditioning and conditioned place preference [36, 61, 85–87]. The sucrose/saccharine consumption free-access paradigm is probably the most extensively used method, as it is not too labour- or time-intensive, has high throughput and aritifacts related to learning, anxiety and locomotion are minimal with this model. Decreased intake and/or preference for palatable solutions is an overall validated behavioural measure of hedonic deficit [9–13, 87]. Insufficient accuracy of the sucrose test in mice is, however, one of the key difficulties in measuring behaviour in chronic stress models of depression [14, 32, 38, 39]. In mice, the sucrose test can typically reveal the differences between groups, but not between individual animals, and is generally considered to result in more variable outcome than in rats. A variety of sucrose test protocols have been proposed to overcome these inconveniences [88–93].
Factors of potential confounds in a free drinking two-bottle sucrose test
Own behavioral data
Source of confounds
Preventing of confounds in testing
Sucrose solution intake is affected by a position of the bottle on preferable or non-preferable side. Weeks of housing with two bottles does not abolish side preference in drinking behaviour
Side preference in drinking
Switching of the bottles in a middle of the test
Individual patterns of absolute water intake in a 10-h test
Large individual variability in daily drinking patterns
High variability in sucrose intake versus water intake in sucrose-naïve mice
Habituation to a sucrose solution Sucrose preference as a measure of hedonic sensitivity
Ceiling values of sucrose preference after massive experience in sucrose ingestion
Sensitization to a sucrose taste
Use of sucrose solution of low concentrations
High inter-individual variability in absolute intake of liquids
Inter-individual differences in metabolic needs
Use of a sucrose preference not sucrose intake as a measure of hedonic sensitivity
Our experiments on mice naive to the taste of sucrose revealed remarkable diversity in animals' reactivity to a sweet taste, which ranged from almost no reaction to excessive sucrose consumption. Repeated exposure to sucrose abolished the first type of behaviour, suggesting that neophobia could underlie this response. A single pre-exposure of mice to concentrated sucrose, a procedure developed in a course of our studies, precluded large variability in their sucrose preference. In different studies, with repeated sessions of the sucrose test, preference and intake of sucrose solutions were found to increase substantially, suggesting that the results of testing in this paradigm depend on the animals' previous experience of sucrose consumption can increase sucrose intake and preference up to ceiling values decreases test's sensitivity [38, 47]. This undesirable effect can be counter balanced by application of sucrose solutions of descending concentrations .
Our results confirm the findings of others, which demonstrate that in comparison to rats, mice generally demonstrate lower values of sucrose preference and sucrose intake, a pronounced neophobic behaviour during the very first exposure to a sucrose solution, essential inter-individual variability in sucrose preference and, especially, in absolute values of daily liquid intake [11–13, 87–93]. Together, the above data show that sucrose preference is a parameter of the sucrose test and is more appropriate than absolute sucrose intake for the analysis of inter-individual differences in hedonic sensitivity in mice. Further, bottle-position preference in mouse drinking behaviour and neophobia together with other factors, may be the cause of essential physiological artifacts in evaluating the sucrose test.
Correcting for limitations in the sucrose preference test in chronic stress-induced anhedonia
We have undertaken several procedural modifications in order to eliminate the above behavioural artifacts. With our proposed protocol, mice are given a free choice between two bottles for 8-24 hours, one with 1%-sucrose solution and another with tap water; the position of the bottles in the cage is switched halfway through this period. At no point during or prior to this are mice deprived of food or water. To minimize the spillage of liquids during the sucrose test, bottles are filled in advance and kept in an up-side-down position for at least 12 hours prior to testing. In order to balance the air temperature between the room and the drinking bottles, they are kept in the same room where the testing takes place. This prevents liquid leakage resulting from increased air temperature and pressure inside the bottles, when they are filled with liquids which are cooler than the room air.
We found that with this method, the error of measurement does not exceed 0.1 ml. This appears to greatly enhance the resolution of the test and more specifically assess hedonic state that takes into account inter-individual variability.
Submissive traits predict stress-induced anhedonia in C57BL6/N mice
A number of studies have shown that it is possible to predict inter-individual variability, in terms of the stress response, by observing an animal's baseline behaviour. Specifically, animals that show high anxiety [41, 60, 63], low open field locomotion [30, 94], freezing response in averse conditions  and decreased exploratory behavior [25, 43] will often have a different stress response to their 'normal' littermates. This phenomenon is attracting the attention of researchers and becoming broadly implemented in fundamental and industrial psychopharmacological research. In our experiments, male social behaviour was shown to predict an individual susceptibility to stress-induced anhedonia in mice: individuals with submissive social traits were found to be more vulnerable to the anhedonic state [44–47]. During a 4-week stress induction period, anhedonia was found to occur earlier in all submissive animals. In one study, after only 3.5 weeks, 100% of submissive mice exhibited lowered sucrose preference (< 65%) and matched a given criterion of anhedonia; only 16.6% of aggressive mice that had undergone the same stressors exhibited the criteria for anhedonia at this stage . The ethological analysis of more than thirty parameters of social behavior in a resident-intruder test, performed with our stress model, revealed reduced scores in aggressive and dominance behaviours in mice predisposed to stress-induced anhedonia . A number of studies have shown that animals with subdominant behavioural characteristics will most frequently exhibit low sucrose preference and anhedonia in similar social defeat models [14, 21, 62, 96–99]. The variability in social traits, which is related to the animal's individual ability to cope with environmental stressors, can be considered as a biological factor of species' adaptation and survival. It can be of even higher significance when animals are placed in stressful conditions and, therefore, of evolutionary advantage in general. Recently identified epigenetic molecular mechanisms are suggested to underlie the distinct response of individual animals to environmental challenges [9, 94, 100].
In our stress paradigm, a resident-intruder test was adapted from the procedure originally proposed by Krsiak and co-authors [101, 102]. Initially, the protocol employs a qualitative criterion of differentiation into submissive vs. non-submissive mice, defined as an absence or presence of attacks towards the partner, respectively. In this test, male mice (C57/BL6N - intruders), after being isolated for 3-5 weeks, and when confronted in a neutral cage with another male mouse which had been group-housed (CD1 - residents), will either show aggressive (non-submissive), timid (submissive) or social behaviour. Aggressive activities of both resident and intruder are characterized by attack and aggressive unrest, frequently accompanied by tail rattling. Timid activities consist of alert posture, escape and defence and are never accompanied by aggressive reactions (attacks). Social behaviour includes social sniff and 'climb and follow', this type of social behaviour excludes attacks between the partners; in our study this behaviour was categorized as non-definable with regard to social submissiveness. A manifestation of submissive and aggressive types of social behaviour in C57BL/6N mice was found to appear irrespective of social traits of CD1 counter partners. According to our data, testing procedures did not induce depressive-like behaviours in the forced swim or sucrose preference tests. Group-housing of male C57BL/6N mice is known to result in aggressive behaviour between cage mates that, importantly, enhances a variability in anxiety-related and a number of other behaviours, as well as having a significant impact on the stress response. We therefore chose to test animals from experimental groups, using them as intruders in a resident-intruder test, thus avoiding the undesirable effects of group housing. While it is more usual to analyze the resident animal in this paradigm, we believe that our protocol of testing social behaviour allowed us to preclude major artifacts in comparing animals from anhedonic and non-anhedonic groups.
Taken together, these data suggest that initial populations with unbalanced social traits could lead to different susceptibilities in terms of the chronic stress model, and may be one of the sources of unstable reproducibility. Our studies have shown that, in terms of development of anhedonia, no differences in initial open field, exploratory rearing, step-down avoidance, novel object or anxiety-like behaviours were exhibited between mice from anhedonic and non-anhedonic groups [38, 39, 44–49]. These data are not always consistent with results published by other groups, which, for example, found a correlation between initial elevated anxiety-like behaviour and enhanced stress-response [41, 63]. The discrepancy between this and our data could be explicated by differences in substrains used and protocols of testing anxiety-like behaviours. Others, however, have largely supported our findings  by showing a lack of differences in various behavioural parameters and baseline sucrose intake and preference between animals from anhedonic and non-anhedonic groups. We believe that in general, balancing of percentage of animals upon a parameter, which is predictive for individual susceptibility to a depressive-like state in any particular chronic stress depression model, can greatly help increase its reliability, especially when the testing of potential anti-depressant treatment is involved.
Identifying and compensating for behavioural artifacts caused by stress-induced hyperlocomotion
Identifying and compensating for behavioural artifacts caused by stress-induced hyperlocomotion
Floating in FST
Open field locomotion
Chronic stress + diazepam
Recent studies described similar phenomenon in several laboratory mouse strains [109–111]. While various effects of chronic stress on general locomotion in rodents were described [34, 96, 112–114, 1115], lighting conditions employed during testing were reported to be a significant factor of general activity in the stressed animals [116–118]. We believe that stress-induced hyperactivity is a typical phenomenon in chronically stressed C57BL/6N mice and is potentially a major source of artifacts in behavioural analysis of chronic stress data and that this can explain previously reported contradictions resulting from similar paradigms.
Increased liquid intake and home-cage locomotion in anhedonic versus non-anhedonic mice: indication of an elevated stress-response?
Stress-induced increases in sucrose and water intake in mice and rats exposed to a prolonged stress have been documented elsewhere [21, 34, 119, 120]. Parallels have been made in the literature between these signs of elevated consummatory behaviour in stressed animals and other indicators of behavioural invigoration, e.g. enhanced swim scores, excessive grooming, increased activity in anxiety paradigms and in other tests [121–123]. Apart from general behavioural invigoration and an increase in consumption scores, the augmentation of general liquid intake observed in chronic stress paradigms is believed to result from a stress-induced polydipsia, increased metabolic needs, diabetes mellitus and altered hormone secretion from both the hypothalamus and hypophysis [21, 124, 125]. Our studies revealed drastic changes in water and sucrose solution consumption as well as home cage locomotion during the course of the chronic stress procedure in C57BL/6N mice. Analysis of animals from the anhedonic and non-anhedonic groups at different phases of stress, and after its termination revealed distinct patterns of dynamics within these parameters [39, 44, 45, 47].
Increased intake of liquids in mice from the anhedonic group was paralleled in our paradigm by sharp increases in home-cage horizontal activity, which was not observed the non-anhedonic group . The latter behaviour was studied using the System and software for Automatic Measurement of Animal Behaviour (SAMAB), where mice were housed individually in specialized cages with infrared detection of horizontal movement.
While the nature of the elevated intake of palatable solutions during chronic stress is unclear, several reports suggest that consumption of sweetened solutions can evoke an antidepressant-like effect in rodents . Interestingly, mice from a group susceptible to stress-induced social avoidance/anhedonia were shown to have higher scores of conditioned place conditioning in comparison to resilient mice . This led to speculation that enhanced sucrose intake and preference in chronically stressed animals might be "adaptation" to stress at its early stages. As such, their increase in mice from an anhedonic group might reflect a "hyperadaptation" to stress in this population, and that the development of anhedonia at the late stage of stress can manifest itself as a state of a "distress" in this subgroup.
Both pronounced elevation of water intake and enhanced home cage locomotion in anhedonic animals may result from general sympathetic activation, induced by chronic stress, and thus, reflect a pronounced response to stress in these animals [21, 126]. Our results also suggest that stress-induced anhedonia in the current mouse model is accompanied by an altered pattern of the day/night activity, which correlates with compromised sleep-wake patterns in depressed patients , and which is not seen in stressed animals without hedonic deficit. These data are in line with other studies which found stress-induced hypertherimia and a decrease in circadian amplitude in a subgroup of mice with a depressive-like state in a social defeat model . Together, differential patterns of liquids intake and home-cage locomotion in anhedonic versus non-anhedonic mice may be reflective of a higher stress susceptibility in the first cohort of animals.
The effects of citalopram in anhedonic and non-anhedonic mice
Experiments with various methods of citalopram administration indicated that in anhedonic animals, chronic administration of drug reduced water intake, which was enhanced in this group of mice, and did not affect this parameter in the non-anhedonic animals (Figure 5C). Interestingly, anhedonic animals from the citalopram-treated stressed group had a higher average body weight than non-anhedonic animals from the same group (Figure 5E). Citalopram restored the body weight of anhedonic mice after the 1st week of post-stress treatment but did not have such an effect in non-anhedonic animals. During weeks 2-4, body mass of the latter group was lower, although not significantly, than in control and citalopram-treated anhedonic aniamls. Prior to citalopram treatment, both anhedonic and non-anhedonic animals exhibited similar patterns of weight loss compared to controls. Restoration of body weight by antidepressant treatment, particularly citalopram, in animal models of depression has been shown to to accompany recovery from a depressive-like state . The distinct effects of citalopram on body weight in anhedonic and non-anhedonic mice may be related to the metabolic differences between these animals: repeated experiments with our model have revealed a general higher baseline body mass in anhedonic than in non-anhedonic animals (Strekalova, unpublished resu lts). These results suggest that citalopram is capable of altering a number of variables in anhedonic animals. This provides more refined analysis of the effects of antidepressant treatment with respect to the states of stress and anhedonia.
In line with available literature, our studies identified distinct physiological and molecular profiles of anhedonic and non-anhedonic groups of mice subjected to stress. As such, the proposed mouse paradigm and other models which enable the segregation of subpopulation of animals with and without a depressive-like pattern can be a tool for addressing the biology of individual susceptibility and resilience to depression. Besides that, this approach provides other valuable advantages in modelling of depressive disorder in animals, as for instance, it allows the differentiation between core and subsidiary depressive features and let to simulate the co-morbidity of depression and other stress-related disorders, e.g., anxiety diseases [78, 79, 131, 132]. This opens new possibilities in pre-clinical studies aimed at the differentiation between therapeutic effects of antidepressants to depression symptoms and other concominant pathological changes. We believe that data on distinct sensitivity to an antidepressant treatment of stressed mice with and without depressive-like syndrome argue for the validity of our paradigm in mimicking such clinical aspects of the disorder.
We feel the importance of emphasizing the fact that the use of internal control in a chronic stress depression paradigm and behavioural assessment of the validity of its definition became possible only when the methodology of chronic stress model in tested strain of mice was essentially modified. These modifications mostly concern (1) the sucrose test protocol in mice, the accuracy of which could be sharply increased to allow distinguish inter-individual differences in the occurrence of signs of anhedonia, and (2) the identification and overcoming of confounds in behavioral testing related to stress-induced hyperlocomotion. Another feature which appeared to be important for more accurate group comparison with the chronic stress model is their balancing upon (3) a percentage of individuals with submissive and dominant social traits, which predicted a susceptibility to a stressed-induced anhedonia in employed strain.
Together, results discussed here argue for the use of a subgroup of individuals who are negative for the induction of a depressive phenotype with experimental paradigms of depression as an internal control, for more advanced modeling of this disorder in animals.
The work on this review was supported by the transnational University Limburg (tUL) foundation, the "NanoBioPharmaceutics" project (the sixth Framework Programme for Research and Technological Development of the EC: EC-FP6), ISAO (N 09501 to T.S), NARSAD (YIA to T.S.), RFBR 11-04-01411 and Fundação para a Ciência ea Tecnologia (FCT), Portugal. All experiments were carried out in accordance with the European Communities Council Directive for the care and use of laboratory animals following approval by the local governmental bodies for animal care and welfare (Regierungspräsidium Karlsruhe, N 35-9185.81/G-48/04; DGV 08; DEC-UM 2009-109). Reproduction of the material presented in this review is permitted by Nova Science Publishers, Inc., 2008 and Lippincott Williams & Wilkins, Behavioral Pharmacology, Strekalova T, Gorenkova N, Schunk E, Dolgov O, Bartsch D. Selective effects of citalopram in the mouse model of stress-induced anhedonia with control effects for chronic stress. 2006;17: 271-287 and by Macmillan Publishers Ltd: Neuropsychopharmacology, Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P. Stressed-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharm 2004; 11: 2007-2017.
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