Elsevier

Psychoneuroendocrinology

Volume 33, Issue 10, November 2008, Pages 1357-1368
Psychoneuroendocrinology

Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal

https://doi.org/10.1016/j.psyneuen.2008.07.010Get rights and content

Summary

Etiopathogenesis of depression and the cause of insensitivity to treatment remain poorly understood, although genetic makeup has been established as a contributing factor. The isogenicity of inbred mouse strains provides a useful tool for investigating the link between genes and behavior or drug response. Hence, our aim was to identify inbred mouse strains (among A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) sensitive to a 9-week period of unpredictable chronic mild stress (UCMS) and, from the fifth week onward, to the reversal effect of an antidepressant (AD) (imipramine, 20 mg/kg/day i.p.) on various depression-related changes: physical, behavioral and neuroendocrine states. UCMS induced a significant deterioration of the coat state (in all the strains), blunted emotional reactivity in the novelty-suppressed feeding (NSF) test (A/J, BALB/c, C57BL/6), and changes in the level of fecal corticosterone metabolites (BALB/c, C57BL/6, DBA, FVB). Imipramine treatment reversed the UCMS-induced alterations of the coat state (BALB/c, DBA), in the NSF test (A/J, BALB/c, C57BL/6) and in fecal corticosterone metabolites (BALB/c, C57BL/6). C3H, CBA and FVB mice were irresponsive to imipramine treatment. It is noteworthy that UCMS-induced physical or behavioral changes occurred without hypothalamo–pituitary–adrenal (HPA) axis alterations in some strains (A/J, C3H, CBA), although the AD-induced reversal of these changes in BALB/c and C57BL/6 was associated with HPA axis normalization. Finally, UCMS is shown to discriminate various alterations and to replicate in a strain-dependent manner diverse profiles reminiscent of human disease subtypes. UCMS may thus enable the selection of strains suitable for investigating specific depression-related features and could be an appropriate model for identifying genetic factors associated with increased vulnerability, specific symptoms of affective disorders, and AD resistance.

Introduction

Major depressive disorder (MDD) is one of the most common and serious health problems of western societies (Murray and Lopez, 1997). MDD is not a well-defined syndrome as it encompasses various subtypes with different patterns of symptoms. While the etiology of MDD is multifactorial and far from perfectly understood, chronic stress or stressful events have been identified among the major environmental factors precipitating depression (Kendler et al., 1999, Riso et al., 2002, Hammen, 2005). This is corroborated by the frequent occurrence of neuroendocrine stress system disturbances in MDD, such as hypercortisolemia and negative feedback impairments of the hypothalamo–pituitary–adrenal (HPA) axis (Arborelius et al., 1999, Holsboer, 2000, Gold and Chrousos, 2002, Barden, 2004). However, an adverse experience does not automatically trigger depressive episodes, but vulnerability is related to the individual's history of stressful life events as well as developmental, genetic and epigenetic factors (Caspi et al., 2003, Craddock and Forty, 2006, Goldberg, 2006, Mill and Petronis, 2007). Likewise, the heterogeneous pattern of symptoms, the presence of HPA disturbances and the frequently observed insensitivity to antidepressants (AD) could stem from the genetic makeup. Knowledge of the genetic basis of these individual differences could help to unravel the source of vulnerability, MDD subtypes and AD resistance. Animal models can be useful to facilitate the discovery of candidate genes.

Studies on inbred mouse strains can provide a powerful tool for understanding the influence of genes in normal and disordered brain function. Interestingly, variability in the response of different inbred mouse strains has been observed in various paradigms such as the forced swimming test (FST) (Bai et al., 2001, Lucki et al., 2001, David et al., 2003), the tail suspension test (TST) (Bai et al., 2001, Liu and Gershenfeld, 2001, Ripoll et al., 2003, Crowley et al., 2005, Liu et al., 2007) or the unpredictable chronic mild stress (UCMS) (Pothion et al., 2004, Ducottet and Belzung, 2005, Mineur et al., 2006). However, sorting strains according to their propensity to develop depression-like behaviors or AD response would appear to be vain in view of the discrepant results of studies. This discrepancy could be due to the diversity of paradigms used. Their common feature is sensitivity to ADs, but they differ in the theoretical background with which they are constructed. The most widely used paradigms are the FST and the TST. Both tests are based on exposure to a single aversive and inescapable situation which induces a behavioral shift from struggling to immobility. A single AD administration can decrease the duration of immobility (Porsolt et al., 1977, Steru et al., 1985, Cryan and Holmes, 2005). The utilization of these tests for AD drug detection gained popularity as pharmacological screening assays, but have been increasingly used for studying neurobiology and pathophysiology as well as for identifying genes causing depression. However, the fact that MDD is a chronic disease and that ADs are only clinically active after a minimum of three weeks treatment makes the validity of such paradigms questionable, particularly when examining the mechanisms involved in the etiology, maintenance and treatment of MDD. Chronic models of depression, such as the UCMS paradigm, could provide an alternative method, avoiding such drawbacks. UCMS is based on subjecting mice to a period (generally five to nine weeks) of mild socio-environmental stressors. This procedure replicates several depression-related behavioral and physiological impairments which can be reversed by chronic, but not acute, AD treatment (Belzung and Surget, 2008): decreased sucrose consumption (interpreted as anhedonia), increased fearfulness/anxiety-related behaviors, altered weight gain, deterioration of the coat (interpreted as the loss of interest in performing customary tasks).

A survey of inbred mouse strains in the UCMS paradigm could be a step toward identifying genes involved in vulnerability to stress exposure, the development of different MDD-associated symptoms, and insensitivity to AD. The major goal of the present study was to identify inbred mouse strains sensitive to the UCMS procedure and in which ADs can reverse various depression-related changes. Mice from seven different strains (A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) were subjected to a 9-week UCMS regimen. From the fifth week onward, vehicle or imipramine (20 mg/kg) was administered i.p. daily. The effects of UCMS and of imipramine treatment were assessed using physical measures (coat state, weight), behavioral tests (novelty-suppressed feeding [NSF] test and actimeter), and the level of fecal corticosterone metabolites was measured to assess HPA axis functioning.

Section snippets

Animals

Male mice from seven inbred strains (A/J, BALB/cByJ, CBA/J, C3H/HeJ, C57BL/6J, DBA/2J, FVB/NJ) were obtained from the Centre d’élevage Janvier (Le Genest Saint Isle, France) and Harlan (Gannat, France). They were aged seven weeks on arrival in our lab. Before the onset of the experiments, all animals were housed in groups of 5 and were maintained under standard laboratory conditions with a 12/12 h light/dark cycle (lights on at 20:00 h), 22 ± 2 °C, food and water ad libitum. The treatment of the

Evaluation of coat state

The coat state was evaluated before the onset of the UCMS regimen and then once a week for nine weeks until the end of UCMS (Fig. 1). The total score was the sum of the scores obtained from seven different body parts (see Section 2); the higher the score, the worse the coat state (Fig. 2).

For the A/J strain, ANOVA revealed significant differences (week, F9315 = 37.18, p < 0.001; group, F2315 = 33.27, p < 0.001; week × group, F18,315 = 11.51, p < 0.001); the 9-week UCMS protocol gave rise to a deterioration

Discussion

This study found strain differences in sensitivity to UCMS, a chronic and naturalistic model of depression, and in response to AD treatment. All seven strains were sensitive to at least one of the UCMS-induced changes, while four strains (A/J, BALB/c, C57BL/6 and DBA) were responsive to at least one of the AD reversal effects. Interestingly, our results revealed different profiles of alterations and imipramine response within the strains (summarized in Table 1). Therefore, each UCMS- and

Conclusion

Chronic models of depression such as the UCMS could be suitable for investigating the neurobiological mechanisms involved in the pathophysiology and treatment of MDD. The UCMS model reproduces features of the human disease and the clinical time-course of AD action. Moreover, our results show that it is possible to distinguish various UCMS-induced alterations which replicate specific symptoms and even subtypes of MDD-associated syndromes, reminiscent of the melancholic or atypical features of

Role of the funding source

No funding was received.

Disclosure/conflict of interest

Y. Ibarguen-Vargas, A. Surget, C. Touma and R. Palme declare that, other than income received from their primary employer, no financial support or payment has been received from any individual or corporate entity over the past three years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. C. Belzung is paid as a consultant for Takeda.

Acknowledgement

We thank Sue Edrich for correction of the manuscript for grammatical and word usage.

Contributors: Y. Ibarguen-Vargas, A. Surget and C. Belzung designed the experiment and wrote the protocol. The UCMS regimen and the data collection (challenge tests) were performed by Y. Ibarguen-Vargas and A. Surget, respectively. C. Touma and R. Palme carried out the analysis of fecal steroid metabolites. Y. Ibarguen-Vargas and A. Surget undertook statistical analysis. Y. Ibarguen-Vargas and A. Surget wrote

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