Animal models of anxiety and depression: how are females different?

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Abstract

The present study examines gender-related issues in the development of animal models of depression and anxiety disorders. Three main issues are discussed: (1) gender differences in the prevalence, etiology, and responses to treatments of neuropsychiatric disorders. An extensive literature reports that mood disorders are more frequent in women compared with men but the great majority of basic research has focused on male rodents as animal models; (2) sex-differences in behavior reflect both organizational and activational effects of steroid hormones, and should be considered in the conceptual frame of the evolutionary theory of sexual selection; (3) animal models of anxiety and depression. Social stress appears to be a good model to induce anxiety-like and depression-like responses, but a large discrepancy in the possibility of inducing social stress in the two genders exists. Reliable models of social stress in females are needed. The effects of social context, as a possible source of stress, on exploration and anxiety in male and female mice were investigated by taking into account the natural history and social behavior of this species. Mice housed individually for 7 days or with siblings were tested in a free-exploratory paradigm of anxiety (where test animals have a choice to stay in their home cage or to explore an open field). Individually housed females showed lower propensity for exploration and a higher level of anxiety compared with group-housed females. Individually housed males tended to show an opposite profile. Animal models may contribute to elucidating some aspect of neuropsychiatric disorders, but they require consideration of the natural life of the animal species studied and of their social behavior in an evolutionary perspective.

Introduction

In western Countries, the proportion of people who experience depression or anxiety of clinical severity is estimated to be about one in five people [1]. The social and economic costs of these mood disorders are relevant; for instance, their prevalence in the prime of life for reproductive-aged women in developed societies results in combined morbidity and mortality estimates, as reported by the WHO, far greater than any other illness [2]. It is therefore understandable that notable efforts have been devoted to understand anxiety and depressive disorders. Animal studies are an essential method to improving our knowledge of these processes, as well as their pharmacological treatment.

In 1872 Charles Darwin [3] laid the conceptual foundation for viewing the defensive behavior of other species as evolutionary precursors to human fear and anxiety reactions. Therefore fear-like reactions in animals are analogous to anxiety-related behaviors in human, thereby providing face validity for the animal model. On the other hand, construct validity implies that human and animal responses are homologous (share common substrates) and thus that the response in question has clinical significance for the disorder being modeled. Human anxiety disorders can be considered as disorders of defence in that there is an inappropriate activation of defensive behavior arising from the erroneous assessment of danger. Human anxiety is reflected in behavioral disturbances including for example, avoidance, escape, non-verbal vocalization and/or hypervigilance [4]. A similar affective state can be observed in animal anxiety. For example, it is well known that when animals are exposed to unfamiliar environments, a series of behavioral and physiological responses may be displayed. At the beginning there may be inhibition of exploratory behavior, freezing, flight, risk assessment, increase in heart rate, urination, defecation, increase in plasma corticosterone levels [5], [6]. These reactions may be interpreted as an activation of the defensive system of the animal in potentially dangerous situations. As the core symptoms of clinical depression involve change in mood, animal models for depression have been more difficult to study but, withdrawal, difficulties in social functioning, lack of active coping are behavioral parameters related to depression [4] and can be observed in animals [7]. It is thus scientifically recognized that animals and humans may share common affective states [6].

However, to understand homologies between animals and humans by means of appropriate animal models we should consider the context in which an animal is placed and the adaptive/functional significance of that behavior in a particular context. This aspect has been often neglected in the traditional experimental approach of behavioral pharmacology (psychopharmacology), which tends to use animals as tools to detect alterations in neural mechanisms without considering whether the social and environmental situations in which animals are tested are ethologically appropriate and thus relevant in terms of adaptive function of behavior. In this context, interindividual variability in the behavioral responses to potentially threatening situations and in the sensitivity to pharmacological treatments may help to understand their underlying mechanisms as well as their adaptive significance. There are many factors that give rise to differences in vulnerability to disease and response to pharmacological treatment. Inequalities in health have been a major concern of researchers on mental and emotional disturbances, and in the last years it has become clear that an important source of variability depends on gender. Sex differences in the prevalence, etiology, and responses to treatments, of neuropsychiatric disorders are indeed well recognized [8].

Section snippets

Gender differences in psychiatric disorders

It is generally acknowledged that alcoholism and other drug abuse, antisocial personality, attention deficit disorders, alcohol use disorders, Tourette's syndrome and completed suicide predominate in men, whereas depression, anxiety, eating disorders, and attempted suicide are more common in women [9], [10], [11], [12], [13]. It is well known that women are over represented in depression; the prevalence of major depression in women is about twice that in men [14], [15], [16], [17], [18], [19],

Sex differences in behavior: proximate and ultimate causations

As Mayr [47] eloquently pointed out, the intertwined but separate issues addressing proximate and evolutionary questions should always be considered in biological research. Thus, when addressing the question of sex differences in emotional and defensive behavior we should consider the proximate mechanisms (e.g. genetic and hormonal basis) and the adaptive significance of such behavioral diversity (i.e. ultimate causation).

The development of sexual dimorphisms in behavior and cognitive function

Animal models for anxiety and depression

It is commonly believed that stress, anxiety and depression are interrelated phenomena. Stress is typically implicated either in the etiology of depressive and anxiety disorders or as consequence of it [80], [81], [82], [83], [84]. Animal models of anxiety and depression are typically based on exposure of animals to a stressful condition (a potential or actual threatening situation) and a specific test for measuring behavioral and physiological responses. Clinical studies suggest that anxiety

Social stress in male and female mice: what is stressful?

Given that many of the animal models of stress attempt to emulate symptoms of anxiety and depressive disorders in humans, it seems important to establish the pervasiveness of sex differences in response to possible social stressors. The aim of the present experiment was to develop an experimental model for social stress in female mice as compared to male mice. To this purpose we examined the effects of social context in the housing environment, as a possible source of stress, on exploration and

Conclusions and perspectives

Anxiety and depression are common psychiatric illnesses often associated with stressful events, and an important source of stress stimuli in humans is of social nature. Because of their putative construct validity with respect to human mood disorders, animal models that involve social stress are particularly appropriate for emulating anxiety and depression, to determine their underlying mechanisms and to find pharmacological treatment. An extensive literature indicates that there are sex

Acknowledgements

This work was supported by grants from MURST and CNR. The author wish to thank the Library Service of the University of Parma and the librarians of the Department of Evolutionary and Functional Biology for providing the data base facilities and the reference-delivery services that made possible to write this review.

References (154)

  • H.M.T. Barros et al.

    Ethopharmacology of imipramine in the forced-swim test: gender differences

    Neurosci Biobehav Rev

    (1998)
  • D.C. Blanchard et al.

    Sex effects in defensive behavior: baseline difference and drug interactions

    Neurosci Biobehav Rev

    (1991)
  • J.A. Gray

    Sex differences in emotional behavior in mammals including man: endocrine bases

    Acta Psychol

    (1971)
  • M. Carlsson et al.

    A regional study of sex differences in rat brain serotonin

    Prog Neuropsychopharmacol Biol Psychiatr

    (1988)
  • A.P. Arnold et al.

    Organizational and activational effects of sex steroids on brain and behavior: a reanalysis

    Hormones and Behavior

    (1985)
  • A. Matsumoto

    Synaptogenic action of sex steroids in developing and adult neuroendocrine brain

    Psychoneuroendocrinology

    (1991)
  • J.J. Liaw et al.

    Changes in tyrosine hydroxylase mRNA levels in medullary A1 and A2 neurons and locus coerulus following castration and estrogen replacement in rats

    Brain Res

    (1992)
  • D.A. Carter et al.

    Modulation of oxytocine secretion by ascending noradrenergic pathways: sexual dimorphism in rats

    Brain Res

    (1987)
  • E. Hampson

    Variations in sex-related cognitive abilities across the menstrual cycle

    Brain and Cognition

    (1990)
  • W.W. Beatty

    Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences

    Horm Behav

    (1979)
  • A.P. Arnold

    Genetically triggered sexual differentiation of brain and behavior

    Horm Behav

    (1996)
  • S.J. Kelly et al.

    Gender differences in brain and behavior: hormonal and neural bases

    Pharmacology Biochemistry & Behavior

    (1999)
  • D. Treit

    Animal models for the study of anti-anxiety agents: a review

    Neurosci Biobehav Rev

    (1985)
  • J.E. Crawley

    Exploratory behavior models of anxiety in mice

    Neurosci Biobehav Rev

    (1985)
  • P. Willner

    Animal models as simulations of depression

    Trends Pharmacol Sci

    (1991)
  • R.D. Porsolt et al.

    Behavioral despair in rats: a new model sensitive to antidepressant treatments

    Eur J Pharmacol

    (1978)
  • R.C. Drugan et al.

    A pretest procedure reliably predicts performance in two animal models of inescapable stress

    Pharmacol Biochem Behav

    (1989)
  • P.S. D'Aquila et al.

    Effects of chronic mild stress on performance in behavioral tests relevant to anxiety and depression

    Physiol Behav

    (1994)
  • R.C. Kessler et al.

    Lifetime and 12 month prevalence of DSM-III-R-psychiatric disorders in the United States: results from the national comorbidity survey

    Arch Gen Psychiatry

    (1994)
  • C.H. Darwin

    The expression of emotions in man and animals

    (1872)
  • Diagnostic and statistic manual of mental disorders

    (1994)
  • D.C. Blanchard et al.

    Risk assessment and animal models of anxiety

  • R.J. Rodgers et al.

    Animal models of anxiety: an ethological perspective

    Braz J Med Biol Res

    (1997)
  • J.M. Koolhaas et al.

    Social stress in rats: an animal model of depression?

    Acta Neuropsychiatrica

    (1995)
  • F. Earls

    Sex differences in psychiatric disorders: origins and developmental influences

    Psychiatric Developments

    (1987)
  • A. Jablensky et al.

    Schizophrenia: manifestations, incidence and course in different cultures: a WHO ten country study

    (1992)
  • Rutter M, Smith D, editors. Psychosocial disorders in young people. Chichester: Wiley,...
  • M.C. Blehar

    Gender differences in risk factors for mood and anxiety disorders: implication for clinical treatment research

    Psychopharmacol Bull

    (1995)
  • E.Z. Hanna et al.

    Gender differences in DSM-IV alcohol use disorders and major depression as distributed in the general population: clinical implications

    Compr Psychiatry

    (1997)
  • R. Gater et al.

    Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings—Report from the World Health Organization collaborative study on Psychological Problems in General Health Care

    Archiv Gen Psychiatry

    (1998)
  • C. Silverman

    The epidemiology of depression

    (1968)
  • S. Nolen-Hoeksema

    Sex differences in unipolar depression: evidence and theory

    Psychopharmacol Bull

    (1987)
  • M. Young et al.

    Gender differences in the clinical features of unipolar major depressive disorders

    J Nerv Ment Dis

    (1990)
  • S.G. Kornstein

    Gender differences in depression: implication for treatment

    J Clin Psychiatry

    (1997)
  • P. Bracke

    Sex differences in the course of depression: evidence from a longitudinal study of a representative sample of the Belgian population

    Soc Psychiatry Psychiatr Epidemiol

    (1998)
  • E.J. Frackiewicz et al.

    Gender differences in depression and antidepressant pharmacokinetics and adverse events

    Ann Pharmacother

    (2000)
  • F.R. Schneier et al.

    Social phobia: comorbidity and morbidity in an epidemiological sample

    Arch Gen Psychiatry

    (1992)
  • L.S. Weinstock

    Gender differences in the presentation and management of social anxiety disorder

    J Clin Psychiatry

    (1999)
  • I.O. Godfroid

    Sex differences relating to psychiatric treatment

    Can J Psychiatry

    (1999)
  • K.A.S. Yonkers et al.

    Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication

    Am J Psychiatry

    (1992)
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