Review article
Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: Relevance to depression

https://doi.org/10.1016/j.pnpbp.2010.03.005Get rights and content

Abstract

Stress is a critical environmental trigger for the development of clinical depression, yet little is known about the specific neurobiological mechanisms by which stress influences the development of depressive symptomatology. Animal models provide an efficient way to study the etiology of human disorders such as depression, and a number of preclinical models have been developed to assess the link between stress, glucocorticoids, and depressive behavior. These mode ls typically make use of repeated exposure to physical or psychological stressors in rodents or other small laboratory animals. This review focuses primarily on a recently developed preclinical model of depression that uses exogenous administration of the stress hormone corticosterone (CORT) in rodents instead of exposure to physical or psychological stressors. Repeated CORT administration in rats or mice produces reliable behavioral and neurobiological alterations that parallel many of the core symptoms and neurobiological changes associated with human depression. This provides an opportunity to study behavior and neurobiology in the same animal, so that the neurobiological factors that underlie specific symptoms can be identified. Taken together, these findings suggest that exogenous CORT administration is a useful method for studying the relationship between stress, glucocorticoids, and depression. Further study with this model may provide important new data regarding the neurobiological bases of depression.

Introduction

Major depression is among the most common of the neuropsychiatric disorders, affecting up to 20% of the population (Kessler et al., 1994). In fact, according to the World Health Organization, depression is reported to be the fourth leading cause of overall disease burden and the leading cause of years lost to disability worldwide in individuals who are 15–44 years of age. Although the core symptoms of depression include low mood and anhedonia (i.e., lack of interest in pleasurable acts), the disorder is characterized by a complex cluster of clinical symptoms that may include psychomotor agitation and/or retardation, decreased energy, altered appetite and weight, nervousness, irritability, sleep disturbances, and cognitive deficits including an impaired ability to think, concentrate, or make decisions (American Psychiatric Association, 2001, Nemeroff, 1998). Moreover, individuals suffering from depression have increased physical illness, decreased social functioning, and a high mortality rate (Nemeroff, 1998). The complexity of this disorder is further compounded by the fact that it often co-occurs with other psychiatric conditions. For example, 51% of those with depression also suffer from anxiety disorders (Kessler et al., 1996), which can have a profound impact on the course of depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicide attempts (Hirschfeld, 2001). It is generally thought that a combination of genetic susceptibility, psychosocial factors, and alterations in neurotransmission and hormone levels influence the development of depression (Kalia, 2005, Nestler et al., 2002b). However, despite sustained clinical and preclinical research efforts, there is still a fundamental lack of understanding about the genetic factors and neurobiological changes that give rise to depressive symptomatology. The primary goal of this review is to examine the influence of stress hormones (i.e., cortisol in humans and corticosterone (CORT) in rodents) and dysregulation of the stress system on the development of depression. Specifically, our discussion will focus on the utility of an exogenous CORT administration animal model as a means to study the relationship between stress, glucocorticoids, and depression.

Section snippets

HPA axis activation under normal circumstances

Although individual vulnerability to developing depression appears to be heritable, a large body of evidence suggests that exposure to stress may be a precipitating factor in developing the disorder (Checkley, 1996). In fact, there are data to suggest that up to 85% of patients experience significant stress prior to the onset of their depressive symptoms (Parker et al., 2003). A key question then becomes, can stress precipitate depression by altering brain structure and function and if so, by

HPA axis dysregulation in depression

Several lines of research in human patients reveal an important connection between excessive HPA axis activation and depression. For example, about half of all depressed patients display hypercortisolemia and disrupted cortisol rhythmicity (Sachar and Baron, 1979), which can be reversed by antidepressant treatment (Holsboer, 2001). Additionally, many hypercortisolemic depressed patients show an attenuated ACTH response to exogenously administered CRF (Amsterdam et al., 1987, Amsterdam et al.,

Structural and functional abnormalities in depression

Although for many years depression had been primarily linked to abnormalities in monoaminergic neurotransmission, it is now well accepted that this condition is characterized by profound alterations in brain structure, function, and responsiveness (Berton and Nestler, 2006, Pittenger and Duman, 2008). Consequently, depressed patients display an inability to cope or adapt to the environment and may be more vulnerable to challenging or stressful experiences. Generally, the pattern of metabolic

Assessing the validity of animal models of depression

Although a large body of clinical evidence suggests a link between chronic stress and depressive illness, these data are correlational and subject to variability. Furthermore, it has been difficult to determine whether the high cortisol levels seen in depressed patients are causal to or a by-product of depression. Therefore, an important question that remains unanswered is whether or not excessive HPA activity and/or high levels of CORT can actually cause depression and if so, by what

Experimenter-applied stress models of depression

A number of experimenter-applied animal models have been developed in an attempt to determine the influence of stress on the development of depression, of which repeated restraint stress and chronic mild stress are two of the most widely used (Kim and Han, 2006). These models will only be discussed briefly here, because the primary purpose of this review is to focus on findings using the exogenous CORT model of depression. In general, repeated restraint stress has been very helpful for studying

Exogenous CORT administration as a preclinical model of depression

Essentially, one of the biggest problems with experimenter-applied stress models such as repeated restraint stress and chronic mild stress is a lack of control over individual differences in responsivity to physical and psychological stressors. Stressful stimuli can differ in their physical qualities (i.e., actual qualities) and in terms of their psychological qualities (i.e., perceived qualities). This may result in differing CORT levels between different rats exposed to the same stressor,

Influence of repeated CORT on depression and anxiety-like behaviors

Although it is impossible to examine all symptoms of depression manifest in patient populations in animal models, a wide range of behavioral measures have been used in an attempt to capture “depression” in rodents (e.g., weight loss, memory impairments, sleep disturbances, open field exploration, anhedonia, and helpless behaviors), of which anhedonia and learned helplessness are the most frequently used. Anhedonia, or the lack of interest in pleasurable acts, is typically inferred by measuring

Influence of repeated CORT on cognition

As discussed previously, depression is often associated with impaired cognition (American Psychiatric Association, 2001), with the largest deficits seen in verbal and spatial working memory and executive function. These are typically forms of memory associated with hippocampal, amygdalar, and/or PFC functioning (Austin et al., 2001, Castaneda et al., 2008, Fleming et al., 2004, Taylor Tavares et al., 2007, Veiel, 1997, Zakzanis et al., 1998). Interestingly, several lines of evidence also

Effects of CORT on structural plasticity

Prolonged exposure to stress induces a considerable degree of structural plasticity in the adult brain, especially in the limbic system, where these changes are accompanied by impairments in learning and memory (McEwen, 2000b, McEwen, 2007, Southwick et al., 2005). Importantly, these neurobiological changes are thought to underlie depressive symptomatology, and have been reliably characterized using exogenous CORT administration. For example, several groups have identified CORT-induced

Considerations when using exogenous CORT to model and study human depression

Although the validity of administering exogenous CORT to emulate a depressive phenotype is now well established, there are a few considerations to be made when choosing to use this model. First, administration of exogenous CORT is not a realistic simulation of stressors encountered in daily life, and the amount of CORT needed to produce a depressive phenotype is often supraphysiological (Johnson et al., 2006). However, this criticism is probably not unique to the CORT model, as the human

Conclusions

Depression is a serious medical condition and a profound public health concern. Although the development of depression is likely due to a combination of factors, understanding the effects, possible triggers, and treatments of the disorder is essential for promoting the well being of affected individuals. The most prominent endocrine change in depressed individuals is a dysregulation of the HPA axis, and a large body of clinical evidence suggests that stress is a significant risk factor in

Acknowledgments

The authors gratefully acknowledge financial support from the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chairs Program of Canada.

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