Hormones, Stress and Depression Marianne B. Müller

Marianne B. Müller

and Florian Holsboer

Summary

Every disturbance of the body, either real or imagined, evokes a stress response.

Essential to this stress response is the activation of the hypothalamic-pituitary- adrenocortical (HPA) system, finally resulting in the release of glucocorticoid hormones from the adrenal cortex. Glucocorticoid hormones, in turn, feed back to this system by central activation of two types of corticosteroid receptors:

the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR).

Whereas a brief period of controllable stress, experienced with general arousal and excitement, can be a challenge and might thus be beneficial, chronically elevated levels of circulating corticosteroid hormones are believed to enhance vulnerability to a variety of diseases, including human affective disorders.

The cumulative evidence makes a strong case implicating corticosteroid receptor dysfunction in the pathogenesis of affective disorders. Corticosteroid receptor dysfunction is followed by changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and vasopressin in hypothalamic neurons. Changes in CRH and vasopressin levels, in turn, determine the responsiveness of the axis to subsequent stressors: increased production of these neuropeptides leads to increased HPA responses to stress and might be associated with an enhanced anxiety state. Although definitive controlled trials remain to be conducted, there is evidence indicating that cortisol-lowering or corticosteroid receptor antagonist treatments, as well as CRH type 1 receptor antagonists, may be of clinical benefit in individuals with major depression. Therefore, a more detailed knowledge of GR and CRH receptor signalling pathways will ultimately lead to the development of novel neuropharmacological intervention strategies.

Kordon et al.

Hormones and the Brain

© Springer-Verlag Berlin Heidelberg 2005

1

Max Planck Institute of Psychiatry, Kraepelinstrasse 2–10, 80804 Munich, Germany

Introduction

The stress hormone (hypothalamic-pituitary-adrenocortical; HPA) system:

corticosteroid hormones are the main actors in restoring homeostasis

Every disturbance of the body, either real or imagined, either physical or psychological, evokes a stress response. This stress response involves a large number of mechanisms and processes which, all together, serve to restrain the body’s defense reactions to stress, so as to restore homeostasis and to facilitate adaptation (Selye 1946). A brief period of controllable stress, experienced with general arousal and excitement, can be a challenge and might thus be beneficial.

In contrast, lack of control and persistent uncertainty in prolonged stressful situations can lead to a chronic state of "distress," resulting in chronically elevated levels of circulating corticosteroid hormones ("stress hormones"), which is believed to enhance vulnerability to a variety of diseases. Chronic exposure to elevated corticosteroid levels has been associated with several pathophysiological conditions, such as dysfunction of the immune system, neurodegeneration in aging and human affective disorders (Chrousos and Gold 1992; Mc Ewen 2000).

Essential to the stress response are hypothalamic paraventricular neurons expressing corticotropin-releasing hormone (CRH) and other co-secretagogues, such as vasopressin. CRH is the primary hypothalamic hypophysiotropic factor regulating both basal and stress-induced release of pituitary corticotropin (ACTH; Vale et al. 1981; Owens and Nemeroff 1991; Aguilera 1998). CRH triggers the immediate release of ACTH from the anterior pituitary, which, in turn, potently stimulates the release of glucocorticoids from the zona fasciculata of the adrenal cortex.

Corticosteroids feed back to the HPA system via two major negative

feedback routes, one directly at the level of the paraventricular nucleus of the

hypothalamus, parvocellular part to control hypothalamic CRH expression

(Erkut et al. 1998) and at the level of the anterior pituitary. This immediate

negative feedback is a fundamental way in which the HPA system is restrained

during stress and activity, and this restraint of HPA activation by glucocorticoids

is rapid and profound (for review, see Herman and Cullinan 1997). In contrast,

induction of CRH expression by increasing glucocorticoid levels has been

described to occur at the level of the central amygdala and the bed nucleus of the

stria terminalis (BNST; for review, see Watts 1996; Schulkin et al. 1998). The latter

is derived embryologically from the amygdala and plays a fundamental role in

the regulation of the HPA system during stress. This “paradoxical’ elevation of

CRH gene expression by glucocorticoids in the central nucleus of the amygdala

and lateral BNST may underlie a number of functional as well as pathological

emotional states in which elevated circulating levels of glucocorticoids are

accompanied by increased anxiety, such as in human affective disorders (for

review, see Holsboer 1995, 2000).

In concert with other components of the stress hormone system, the action of corticosteroid hormones displays two modes of operation (for review, see de Kloet et al. 1998). On the one hand, corticosteroids maintain basal activity of the HPA system and control the sensitivity or threshold of the system’s response to stress. On the other hand, corticosteroid feedback helps to terminate stress-induced HPA system activation and to restrain the stress response.

Corticosteroid hormones, therefore, facilitate an individual‘s ability to cope with, adapt to and recover from stress.

Due to their lipophilic nature, glucocorticoid hormones are able to easily penetrate through cell membranes into every cell of the body. Physiological control of the access of endogenous glucocorticoids into the brain is an important issue, all the more so as both glucocorticoid overexposure and glucocorticoid deficiency have been shown to potentially impair and endanger neuronal integrity and function. Accordingly, the potentially disruptive effects of corticosteroids in control of brain function and behaviour have received much attention over the last years (Uno et al. 1989; Lucassen et al. 2001; Müller et al. 2001). In this context, the recent findings that endogenous corticosteroid hormones are substrates of the multidrug-resistance gene 1-type P-glycoproteins are of particular importance (Meijer et al. 2000; Karssen et al. 2001; Müller et al.

2003a): mdr 1-type P-glycoproteins are highly expressed at the blood-brain- barrier to protect the central nervous system against the entry and accumulation of a wide range of toxic xenobiotics and drugs by actively transporting them against a concentration gradient.

Glucocorticoid receptors (GRs) occur everywhere in the brain but are most abundant in hypothalamic CRH neurons and pituitary corticotropes.

Mineralocorticoid receptors (MRs), in contrast, are highly expressed in the hippocampus and, at lower expression levels, in hypothalamic sites involved in the regulation of salt appetite and autonomic outflow. Interestingly, the MRs and GRs are co-localized in those brain structures that are involved in the regulation of fear and anxiety, such as hippocampus, septum and amygdala.

The two corticosteroid receptor types differ not only in their neuroanatomical distribution but also in their affinity and binding capacity for corticosteroids:

the MR binds GCs with a t10-fold higher affinity than does the GR (Reul and

de Kloet 1985). These findings on corticosteroid receptor diversity led to the

working hypothesis that the tonic influences of corticosterone are exerted via

hippocampal MRs, whereas the additional occupancy of GRs with higher levels

of corticosterone, e.g., following stress, mediates feedback actions aimed to

restrain HPA system activation. Thus, the balance in MR- and GR-mediated

effects exerted by corticosterone seems to be critical for homeostatic control (de

Kloet et al. 1997,1998).

Impaired stress hormone regulation – a risk factor for depression?

Several research groups formulated a hypothesis relating aberrant stress hormone regulation to causality of depression (for review, see Holsboer 1999, 2000). The reason for HPA hyperactivity and, in particular, for enhanced synthesis and release of CRH in depression is not yet clear. Genetic and experience-related factors may interact to induce manifold changes in corticosteroid receptor signaling, finally resulting in hypersecretion of both CRH and vasopressin (Raadsheer et al. 1994; Purba et al. 1996; de Kloet et al. 1998; Müller et al. 2000).

A considerable amount of evidence has been accumulated suggesting that normalization of the HPA system might be the final step necessary for stable remission of the disease (Holsboer and Barden 1996; Zobel et al. 1999; Holsboer 2000). On the basis of these findings, it has been further hypothesized that antidepressants may act through normalization of HPA system function (for review, see Holsboer 2000).

Prominent HPA abnormalities among patients with major depression are increased numbers of ACTH and cortisol secretory pulses, which is also reflected in elevated urinary cortisol secretion rates (Rubin et al. 1987).

These studies were complemented by different neuroendocrine function tests, including the dexamethasone suppression test (DST) and the combined dexamethasone-CRH-challenge test (dex-CRH test). This dex-CRH-test, combining the DST with CRH stimulation, has been shown to be a sensitive test for detecting HPA dysregulation in patients with affective disorders. In fact, Heuser and co-workers concluded from their studies that the sensitivity of this combined dex-CRH test (i.e., the likelihood to differentiate between normal and pathological states) is above 80%, depending on age and gender (Heuser et al. 1994). Whereas CRH-elicited ACTH response is blunted in depressives, dexamethasone pretreatment produces the opposite effect and paradoxically enhances ACTH release following CRH. Similarly, CRH-induced cortisol release is much higher in dexamethasone-pretreated patients than following a challenge with CRH alone. Moreover, the combined dex-CRH test has proved to be particularly useful as a predictor of increased risk for relapse: in those patients where the neuroendocrine abnormality persists, the risk of relapse or resistance to treatment is much higher (Holsboer et al. 1987; Heuser et al. 1996;

Zobel et al. 1999).

Such a HPA disturbance in feedback control can be acquired as a result of stressful life experiences and can be compounded by age (Brunson et al.

2001), or it can be genetically predetermined at all levels involved in fine-tuned

neuroendocrine regulation. Depressive and anxiety disorders are likely to

have significant genetic components, as suggested by familial segregation of

these disorders and twin and adoption studies. It is possible, however, that the

genetic component is not an independent risk factor for the development of these

disorders but rather a vulnerability factor predisposing for the development of

affective disorders following stress exposure. Likewise, genetic factors may also

protect an individual from stress-related illness. Genetic and experience-related factors may interact to induce manifold changes in corticosteroid receptor signaling, finally resulting in hypersecretion of both CRH and AVP (Raadsheer et al. 1994; Purba et al. 1996; de Kloet et al. 1998; Müller et al. 2000). In this context, the data from the Munich Vulnerability Study are of particular interest (Holsboer et al. 1995; Modell et al. 1997, 1998). This study investigated whether the HPA feedback disturbance observed among patients with major depression is present in otherwise healthy individuals who are at high risk for psychiatric disorders because they have a first-degree relative with an affective illness.

The Munich Vulnerability Study revealed that subjects who never suffered from a psychiatric disorder, but belong to families with a considerably high genetic load for depression, may display abnormal responses to the combined dex-CRH-challenge test (Holsboer et al. 1995; Lauer et al. 1998; Modell et al.

1998). In the absence of any previous depression in these individuals, or other life events or lifestyles that would explain the functional corticosteroid receptor changes as an enduring adaptation to major stress, the findings from this study are best understood as indicating a genetically transmitted risk factor, possibly rendering these individuals susceptible to affective disorders. In a follow-up study, 14 of the initial 47 high-risk probands were re-examined about four years after the index investigation and showed surprisingly constant results in the combined dex-CRH challenge test, so that one of the requirements for a vulnerability marker is fulfilled (Modell et al. 1998).

Whereas genetic linkage studies so far reject the glucocorticoid receptor gene as a possible gene of inherited pathology (Detera-Wadleigh et al. 1992; Mirow et al. 1994; Morisette et al. 1999; Moutsatsou et al. 2000), the recent development of refined genetic technologies opens up the possibility for large-scale screening of single nucleotide polymorphisms (SNPs; Syvanen 2001; Cowan et al. 2002).

These SNPs are highly abundant and are estimated to occur at one out of every 1,000 bases in the human genome. Depending on where a SNP occurs, it might have different consequences at the phenotypic level. The reason for the current interest in SNPs is the hope that they could be used as markers to identify genes that predispose individuals to complex, polygenic disorders. A recent investigation provided evidence that carriers of a specific polymorphism (ER22/23EK) in the GR gene are less sensitive to the suppressive effects of low- dose dexamethasone (van Rossum et al. 2002) and are suspected to be relatively more resistant to the effects of GC, with respect to the sensitivity of adrenal feedback mechanisms, than are non-carriers. Considering the aforementioned implications of HPA system dysregulation for the development and maintenance of affective disorder, those functionally relevant polymorphisms of the GR, therefore, may alter an innate setpoint for susceptibility to stress-associated psychiatric disorders (DeRijk et al. 2002).

As outlined above, there is robust evidence for a hyperactivtity of the

HPA system in human affective disorders, and it has been proposed that

hypercortisolemia is in some way integral to the pathogenesis and maintenance of psychopathology and cognitive deficits in these diseases. It is, therefore, not surprising that research into novel therapeutic approaches to depression has focused on strategies designed to modulate the effects of hypercortisolemia and/or the mechanisms underlying this phenomenon (Murphy 1997; McQuade and Young 2000). Antiglucocorticoid drugs and approaches in the treatment of human affective disorder include the administration of steroid-synthesis inhibitors, such as ketoconazole, metyrapone and aminogluthetimide (e.g., Ravaris et al. 1988; Malison et al. 1999; Wolkowitz et al. 1999) or GR antagonists, such as mifepristone (Belanoff et al. 2002).

Pathological anxiety is a frequent concomitant of major depression.

Moreover, there is a longstanding debate about whether anxiety and depression constitute different aspects of the same disorder (“continuum hypothesis”) or distinct, yet overlapping, conditions. Anxiety-related behavior is one of the most important, highly conserved behaviors among all kind of species that can be reliably measured in specific experimental paradigms in rodents. Increased CRH neuronal activity has been hypothesized both in major depression and anxiety disorders. The crucial role of CRHR1 in mediating anxiety-related behavior was confirmed in transgenic mice with a functional null mutation of CRHR1 (Smith et al. 1998; Timpl et al. 1998). Most recently, using a brain area-specific conditional knockout mouse line, researchers showed that limbic Crhr1 neuronal circuitries mediate anxiety-related behavior, and that this anxiolytic effect is independent of HPA system activity (Müller et al. 2003b). These results, therefore, allow us to genetically dissect CRH/Crhr1 neuronal pathways modulating behavior from those regulating neuroendocrine function, underlining the importance of limbic CRH/Crhr1 neuronal pathways as a promising pharmacological target for the treatment of human affective disorders, such as major depression or the consequences of early-life stress (Holsboer 1999; Keck and Holsboer 2001).

One such selective CRHR1 antagonist, NBI-30775 (also referred to as R121919), was first shown to decrease anxiety- and fear-related behaviors in response to stress in rodents (Keck et al. 2001). In an open-label proof of concept study, 20 patients with major depression receiving NBI-30775 experienced significant reductions in depression and anxiety ratings, whereas neither basal nor CRH-stimulated HPA system activity was impaired (Zobel et al. 2000).

Besides pharmacological and other more traditional approaches to examine

stress-anxiety interactions in animal models, an alternative way is to directly

modify neurobiological systems involved in the stress response and to examine

the effects of these manipulations on anxiety-related behaviors. As mentioned

before, the primary candidates for these types of manipulations are the various

components of the HPA system (for review, see Müller et al. 2002; Müller and

Keck 2002). The ability to generate mice with specific mutations or complete

deletions of certain genes of interest through homologous recombination in

embryonic stem cells has facilitated the study of many biological processes, from

embryogenesis to animal behavior. The generation of genetically engineered mice (e.g., "conventional" and "conditional" knock-outs) has allowed us to specifically target individual genes involved in stress hormone regulation. The identification and detailed characterization of these molecular pathways will ultimately lead to the development of novel neuropharmacological intervention strategies.

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