Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse

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Abstract

Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response.

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.

References (91)

  • M. Freire-Garabal et al.

    Effects of alprazolam on cellular immune response to surgical stress in mice

    Cancer Lett

    (1993)
  • M. Freire-Garabal et al.

    Effects of fluoxetine on the activity of phagocytosis in stressed mice

    Life Sci

    (2002)
  • N. Gobshtis et al.

    Antidepressant-induced undesirable weight gain: prevention with rimonabant without interference with behavioral effectiveness

    Eur J Pharmacol

    (2007)
  • X. Gonda et al.

    High anxiety and migraine are associated with the s allele of the 5-HTTLPR gene polymorphism

    Psychiatry Res

    (2007)
  • F.G. Graeff et al.

    Role of 5-HT in stress, anxiety, and depression

    Pharmacol Biochem Behav

    (1996)
  • J.A. Hastings et al.

    Influence of leptin on neurotransmitter overflow from the rat brain in vitro

    Regul Pept

    (2002)
  • A. Holmes

    Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

    Neurosci Biobehav Rev

    (2008)
  • A. Inui

    Feeding and body-weight regulation by hypothalamic neuropeptides — mediation of the actions of leptin

    Trends Neurosci

    (1999)
  • F. Jansen et al.

    Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood

    Behav Brain Res

    (2010)
  • H. Jarrell et al.

    Polymorphisms in the serotonin reuptake transporter gene modify the consequences of social status on metabolic health in female rhesus monkeys

    Physiol Behav

    (2008)
  • A.J. Keeney et al.

    Alterations in core body temperature, locomotor activity, and corticosterone following acute and repeated social defeat of male NMRI mice

    Physiol Behav

    (2001)
  • E.A. Kirk et al.

    Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: searching for level and variability genes

    J Lipid Res

    (1995)
  • V. Krishnan et al.

    Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions

    Cell

    (2007)
  • T.M. Loftus

    An adipocyte-central nervous system regulatory loop in the control of adipose homeostasis

    Semin Cell Dev Biol

    (1999)
  • Z.W. Lu et al.

    Influence of a psychogenic and a neurogenic stressor on several indices of immune functioning in different strains of mice

    Brain Behav Immun

    (1998)
  • F. Marini et al.

    Single exposure to social defeat increases corticotropin-releasing factor and glucocorticoid receptor mRNA expression in rat hippocampus

    Brain Res

    (2006)
  • A. Moles et al.

    Psychosocial stress affects energy balance in mice: modulation by social status

    Psychoneuroendocrinology

    (2006)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • M.J. Nunez et al.

    Effects of fluoxetine on cellular immune response in stressed mice

    Neurosci Lett

    (2006)
  • D.J. Nutt et al.

    Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders

    Eur Neuropsychopharmacol

    (1999)
  • P. Prolo et al.

    Leptin

    Int J Biochem Cell Biol

    (1998)
  • A. Raab et al.

    Continuous social defeat induces an increase of endogenous opioids in discrete brain areas of the Mongolian Gerbil

    Peptides

    (1985)
  • M. Razzoli et al.

    Different susceptibility to social defeat stress of BalbC and C57BL/6J mice

    Behav Brain Res

    (2011)
  • J.W. Richardson-Jones et al.

    5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants

    Neuron

    (2010)
  • T. Sakaguchi et al.

    Effect of norepinephrine, serotonin and tryptophan on the firing rate of sympathetic nerves

    Brain Res

    (1989)
  • D.A. Sandoval et al.

    Leptin metabolic control and regulation

    J Diab Complications

    (2003)
  • A. Serretti et al.

    The influence of serotonin transporter promoter polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments

    Prog Neuropsychopharmacol Biol Psychiatry

    (2005)
  • A. Sgoifo et al.

    Social stress, autonomic neural activation, and cardiac activity in rats

    Neurosci Biobehav Rev

    (1999)
  • N. Shanks et al.

    Norepinephrine and serotonin alterations following chronic stressor exposure: mouse strain differences

    Pharmacol Biochem Behav

    (1994)
  • P.E. Stokes et al.

    Fluoxetine tenth anniversary update: the progress continues

    Clin Ther

    (1997)
  • R. Tao et al.

    Effects on serotonin in rat hypothalamus of d-fenfluramine, aminorex, phentermine and fluoxetine

    Eur J Pharmacol

    (2002)
  • D. Wahlsten

    Heritable aspects of anomalous myelinated fibre tracts in the forebrain of the laboratory mouse

    Brain Res

    (1974)
  • D.T. Balu et al.

    Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of chronic antidepressant treatments

    Neuropsychopharmacology

    (2009)
  • C.S. Barr et al.

    The utility of the non-human primate; model for studying gene by environment interactions in behavioral research

    Genes Brain Behav

    (2003)
  • A. Bartolomucci et al.

    Metabolic consequences and vulnerability to diet-induced obesity in male mice under chronic social stress

    PLoS ONE

    (2009)
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