Animal models of anxiety and depression: how are females different?
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)
- et al.
Gobal mortality, disability and the contribution of risk factors: global burden of disease study
Lancet
(1997) - et al.
Gender differences in depression in primary care
Am J Obstet Gyneco
(1995) - et al.
Gender differences in the prevalence of depression: a survey in primary care
J Affect Disord
(1999) - et al.
Sex differences in depression: a role for preexisting anxiety
Psychiatry Res
(1995) - et al.
Women and anxiety
- et al.
Gender differences in human pharmacokinetics and pharmacodynamiks
J Adolesc Health
(1994) - et al.
The actions of diazepam and serotonergic anxiolytics vary according to the gender and the estrus cycle phase
Pharmacol Biochem Behav
(1990) - et al.
Sex differences in behavioral despair: relationships between behavioral despair and open field activity
Physiol Behav
(1991) - et al.
Sex differences in open field behavior in response to the beta-carboline FG7142 in rats
Physiol Behav
(1993) - et al.
Anxiolytic actions of diazepam, but not buspirone, are influenced by gender and the endocrine stage
Behav Brain Res
(1997)
Ethopharmacology of imipramine in the forced-swim test: gender differences
Neurosci Biobehav Rev
Sex effects in defensive behavior: baseline difference and drug interactions
Neurosci Biobehav Rev
Sex differences in emotional behavior in mammals including man: endocrine bases
Acta Psychol
A regional study of sex differences in rat brain serotonin
Prog Neuropsychopharmacol Biol Psychiatr
Organizational and activational effects of sex steroids on brain and behavior: a reanalysis
Hormones and Behavior
Synaptogenic action of sex steroids in developing and adult neuroendocrine brain
Psychoneuroendocrinology
Changes in tyrosine hydroxylase mRNA levels in medullary A1 and A2 neurons and locus coerulus following castration and estrogen replacement in rats
Brain Res
Modulation of oxytocine secretion by ascending noradrenergic pathways: sexual dimorphism in rats
Brain Res
Variations in sex-related cognitive abilities across the menstrual cycle
Brain and Cognition
Gonadal hormones and sex differences in nonreproductive behaviors in rodents: organizational and activational influences
Horm Behav
Genetically triggered sexual differentiation of brain and behavior
Horm Behav
Gender differences in brain and behavior: hormonal and neural bases
Pharmacology Biochemistry & Behavior
Animal models for the study of anti-anxiety agents: a review
Neurosci Biobehav Rev
Exploratory behavior models of anxiety in mice
Neurosci Biobehav Rev
Animal models as simulations of depression
Trends Pharmacol Sci
Behavioral despair in rats: a new model sensitive to antidepressant treatments
Eur J Pharmacol
A pretest procedure reliably predicts performance in two animal models of inescapable stress
Pharmacol Biochem Behav
Effects of chronic mild stress on performance in behavioral tests relevant to anxiety and depression
Physiol Behav
Lifetime and 12 month prevalence of DSM-III-R-psychiatric disorders in the United States: results from the national comorbidity survey
Arch Gen Psychiatry
The expression of emotions in man and animals
Diagnostic and statistic manual of mental disorders
Risk assessment and animal models of anxiety
Animal models of anxiety: an ethological perspective
Braz J Med Biol Res
Social stress in rats: an animal model of depression?
Acta Neuropsychiatrica
Sex differences in psychiatric disorders: origins and developmental influences
Psychiatric Developments
Schizophrenia: manifestations, incidence and course in different cultures: a WHO ten country study
Gender differences in risk factors for mood and anxiety disorders: implication for clinical treatment research
Psychopharmacol Bull
Gender differences in DSM-IV alcohol use disorders and major depression as distributed in the general population: clinical implications
Compr Psychiatry
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
The epidemiology of depression
Sex differences in unipolar depression: evidence and theory
Psychopharmacol Bull
Gender differences in the clinical features of unipolar major depressive disorders
J Nerv Ment Dis
Gender differences in depression: implication for treatment
J Clin Psychiatry
Sex differences in the course of depression: evidence from a longitudinal study of a representative sample of the Belgian population
Soc Psychiatry Psychiatr Epidemiol
Gender differences in depression and antidepressant pharmacokinetics and adverse events
Ann Pharmacother
Social phobia: comorbidity and morbidity in an epidemiological sample
Arch Gen Psychiatry
Gender differences in the presentation and management of social anxiety disorder
J Clin Psychiatry
Sex differences relating to psychiatric treatment
Can J Psychiatry
Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication
Am J Psychiatry
Cited by (462)
Behavioural-type coping strategies in leisure dromedary camels: factors determining reactive vs. proactive responses
2024, Applied Animal Behaviour ScienceMitochondrial morphology in the mouse adrenal cortex: Influence of chronic psychosocial stress
2024, PsychoneuroendocrinologyGenotype determining aerobic exercise capacity associates with behavioral plasticity in middle-aged rats
2023, Behavioural Brain ResearchChronic social instability stress down-regulates IL-10 and up-regulates CX3CR1 in tumor-bearing and non-tumor-bearing female mice
2022, Behavioural Brain ResearchCitation Excerpt :This highlights the importance of studying the response to a variety of stressors also in females [120,65]. Despite existing evidence regarding sex differences in the neural, immune and behavioral response to CSS, most of the models developed for the study of its effects in rodents, such as the social defeat model, work optimally in males [45,52], but are not suitable for inducing CSS in females, as they do not reveal territorial aggression [31,78]. Consequently, knowledge of the specific mediators involved in the possible negative effects of CSS in females is very limited.