Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse
Research Highlights
►The study illustrates how mouse strains differing in baseline emotionality respond to social defeat stress, thus highlighting strain-specific coping strategies. ►In particular, C57BL6/J and BalbC mice showed predominant alterations supportive of metabolic and behavioral susceptibility, respectively. Strain-specific outcomes of a chronic fluoxetine treatment in several domains related to long-term stress responses and mood disturbances were also demonstrated. ►This approach may provide a valid experimental tool to study different susceptibility levels to stress and vulnerability to its deleterious consequences, aiming at establishing a translational model with relevance for human pathology.
Introduction
The most recent translational biomedical research has been focused on the neurobiology of the individual perception of adverse life events and on its role in the development of psychiatric conditions in vulnerable subjects (Krishnan et al., 2007, Jarrell et al., 2008, Miller et al., 2008, Balu et al., 2009, Gillespie et al., 2009, Lagace et al., 2010, Wood et al., 2010). The complexity of this matter is further increased having to factor in the individual variability in the response to psychotropic drugs, a phenomenon potentially related to different levels of stress vulnerability (Rush et al., 2006, Richardson-Jones et al., 2010).
Multiple experimental approaches can be applied to better understand the biological nature of the proposed link between stress vulnerability and variability in the response to psychotropic drugs (Rutter, 2006, Richardson-Jones et al., 2010). In particular, social stress such as social defeat in rodents is a significant and ethologically relevant experience in that, even when faced once, it can have persistent behavioral and neurobiological effects (Miczek et al., 1999, Marini et al., 2006). In mice the chronic exposure to social defeat stress has the potential to segregate defeated subjects into susceptible and unsusceptible populations, on the basis of a considerable individual variance to social defeat behavioral outcomes (Krishnan et al., 2007). Alternatively, the comparison of stress effects across different mouse strains may enable the identification of the stress-induced neurochemical alterations promoting depressive-like phenotypes; several behavioral inter-strain differences and the relative contribution of genetic factors to stress/anxiety reactions have been repeatedly demonstrated (reviewed in Crawley et al., 1997).
We have recently highlighted strain-specific social defeat coping styles by subjecting mice of two inbred lines to a repeated social defeat procedure (Razzoli et al., 2011). The C57BL/6J and BalbC strains were chosen for their differential stress reactivity, as the former is reported to be stress-resilient, exhibiting a lower level of anxiety and emotionality compared to the latter (Shanks et al., 1994, Crawley et al., 1997, Belzung et al., 2001), and we were able to highlight a greater metabolic susceptibility to chronic social defeat stress in C57BL/6J and a greater behavioral susceptibility in BalbC defeated subjects.
Thus we sought to expand the translational potential of these results by assessing the efficacy of a standard serotonergic antidepressant treatment in this social defeat model based on several assumptions. Firstly, variations in serotonin (5-HT) neurotransmission are included among the genetic factors that modulate individual differences in the stress response as well as the potential adverse health consequences associated with chronic stress exposure (Barr et al., 2003, Graeff et al., 1996, Price and Lucki, 2001, Jarrell et al., 2008, Jansen et al., 2010). Secondly, a deficient serotonergic system in the brain has been related to increased risk of developing psychiatric pathologies (Owens and Nemeroff, 1994, Melke et al., 2001, Lesch et al., 1996, Gonda et al., 2007, Holmes, 2008). Thirdly, the therapeutic potential of agents increasing the synaptic concentration of 5-HT or enhancing the serotonergic neurotransmission is observed in the treatment of mood and eating disorders (reviewed in Butler and Meegan, 2008, Capasso et al., 2009). These agents include selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, that act by blocking the 5-HT transporters, thus prolonging the elevation of extracellular 5-HT in response to activation of serotonergic neurons (Nutt et al., 1999). Fluoxetine represents the prototypical SSRI whose therapeutic applications, owing to the manifold effects of 5-HT in the brain, expand beyond depression to the treatment of anorexia and bulimia nervosa, obsessive–compulsive disorder, premenstrual dysphoria and generalized anxiety disorder (Stokes and Holtz, 1997, Wong et al., 2005).
Nonetheless, the human response to antidepressant treatment is highly variable. Complete remission of depression occurs in only 50–60% of patients and considerable individual variability is assessed in the clinical efficacy of any given treatment (Nestler et al., 2002, Trivedi et al., 2006), both of which could be accounted for by, amongst others, polymorphisms in genes involved in monoaminergic signaling (Serretti et al., 2005, Binder and Holsboer, 2006).
It has been proposed that the variation in the response of different mouse strains to fluoxetine resembles the observed variation in human response to SSRIs treatment (Rush et al., 2006, Miller et al., 2008). Hence, to gain insight into the neurobiological factors conferring vulnerability or resiliency to stress, with its implications in psychiatric diseases and treatment response, we evaluated the long-term consequences of social defeat stress and of a chronic fluoxetine treatment in C57BL/6J and BalbC mice in a variety of behavioral, physiological, endocrine, and immune parameters relevant to stress responses and depressive-/anxiety-like states.
Section snippets
Animals
Forty C57BL/6J and 40 BalbC male mice (Charles River Labs, Calco, Italy) weighing 18–20 g at the beginning of the experiments served as experimental subjects. Mice were housed under constant temperature (21 ± 2 °C) and a 12 h/12 h light/dark cycle (lights on 06.00–18.00). Food and water were available ad libitum.
All experimental procedures were carried out in accordance with Italian law (Legislative Decree no.116, 27 January 1992), which acknowledges the European Directive 86/609/EEC, and were fully
Serum fluoxetine levels
Serum fluoxetine levels, assessed in a subset of C57BL/6J mice at the end of the chronic drug treatment, corresponded to 343.50 ± 74.93 ng/mL. It is important to notice that the serum levels of fluoxetine achieved in our conditions were consistent with previous reports (Dulawa et al., 2004); values for the 10 mg/kg/day dose were within the range found in patients taking 20–80 mg/day Prozac (100–700 ng/mL), at a time when the steady state has long been achieved (Koran et al., 1996, Santarelli et al.,
Discussion
The present experiments demonstrated strain-specific responses to social defeat and to the associated chronic fluoxetine treatment. In general, considering each strain response to the experimental procedure, while C57BL/6J showed alterations in metabolic parameters supportive of a predominantly metabolic susceptibility, mice belonging to the BalbC strain demonstrated to be mostly behaviorally sensitive, given their social avoidance and FST responses. A similar diverging reactivity to the
Acknowledgements
The authors wish to thank Claudia Granato, Alessia Guidi, Claudia Mundi, Valentina Pavoni, Alessandro Poffe and Claudio Righetti for their excellent technical assistance in the conducting of experiments.
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