ReviewCorticosteroids in relation to fear, anxiety and psychopathology
Introduction
Fear can be a very functional emotion. The elicitation of fear at the right moment, e.g. when an animal encounters a predator, is needed for rapid evasive action in which adrenal hormones play a crucial role. The body's immediate physiological reaction is often characterized by activation of the adrenomedullary system, resulting in the release of catecholamines; these rapidly prepare the body for the metabolic requirements of ‘fight or flight’ reactions [1]. The secondary stress response is slower and is characterized by the release of corticosteroids from the adrenal cortex, via a cascade of events in the limbic-hypothalamo-pituitary adrenal (LHPA) axis. Circulating corticosteroids reach a peak some minutes after the stressful event [2]. After ‘fight or flight’ responses, corticosteroids are required to re-establish homeostasis via feedback mechanisms. The animal needs to consolidate its memories of the predator's appearance, location, smell and sound, because such information may predict the occurrence and nature of the next encounter and, thereby, maximize the likelihood of survival. Corticosteroids act to facilitate behavioral adaptation via their effect on the consolidation and potentiation of fear or the facilitation of extinction of avoidance (see below).
Not all animals react similarly in fearful situations. It has been shown that there is a close link between the emotional evaluation of a stressful situation and an individual's coping strategy and vice versa [3], [4]. Some animals generally react in an active fashion (‘fight or flight’) but others are more likely to show behavioral inhibition during acute fear [5]. They cease all ongoing activities, such as feeding, drinking or exploring and they immediately freeze when a predator or other source of danger is detected thereby reducing the likelihood of detection and attack from a predator [6], [7], [8]. If caught, they may show a tonic immobility (death feigning) response; this often results in the predator losing interest and moving away [9], [10]. During freezing or tonic immobility the animals remain very alert [10]. There is a growing body of evidence that corticosteroid receptors play a critical role in mediating freezing behavior (see below).
It is important to realize that behavior is not just driven by reactive demands, but also by anticipatory responses. Behavioral adjustments are often made in anticipation of changing demands. There is mounting evidence that corticosteroids are involved in such allostasis or feed-forward regulation [11], [12], [13] (see below).
Excessive fear can lead to psychopathology and mental suffering as well as physical damage [6], [8], [11], [12], [13]. The quest to understand brain mechanisms underlying fear (caused by real and immediate dangers), anxiety (caused by unreal or imagined threats) and psychopathology has led many investigators over the past three decades to study the interactions between corticosteroids and the brain [14], [15], [16], [17], [18], [19], [20], [21]. Contrasting effects of corticosteroids (corticosterone or cortisol depending on species) on fear, anxiety and depressed mood have been described and this has often been a source of confusion [17], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. This is partly due to the fact that corticosteroids do not regulate emotional behavior, rather they induce chemical changes in particular sets of neurons, making certain behavioral outcomes more likely in a certain context, as a result of the strengthening or weakening of particular neural pathways [33], [34]. Therefore, special attention will be given here to those conditions that render the actions of corticosteroids on emotionality so unique.
First, one has to consider when corticosteroids exert their effects: in anticipation of a threat, in the presence of a threat, or after it has disappeared. Depending on the context and the phase of the stress response, corticosteroids may produce opposite effects on emotional behavior via different receptors in the brain. Therefore, the timing and duration of the hormone action, as well as its context, need to be considered when designing and interpreting the results of behavioral experiments performed in the laboratory.
Second, a growing body of evidence suggests that several emotional behavioral tests measure different types of defensive behaviors (e.g. freezing, risk assessment, burying etc.) and different aspects of fear and anxiety (e.g. fear conditioning and consolidation, fear extinction, fear potentiation) and that these processes may involve different brain systems, both in terms of neuroanatomy and neurochemistry [35], [36], [37]. Therefore, the action of the hormone needs to be studied using different tests of emotionality as well as in the presence of unconditioned and conditioned stressors.
Here I emphasize the effects of corticosteroids on fear, anxiety and psychopathology. Only a selected number of animal models are discussed, but in detail. Other investigators have focussed on corticosteroid effects in cognition and memory [38], [39], [40].
Adrenal steroids can exert many behavioral actions because the central nervous system not only organizes the hormonal response, but also serves as a major target organ for the released corticosteroids [41]. Béla Bohus was a pioneer in this field and already in the early seventies he wrote: “the little hormonal devil touches the large hippocampus to serve the process of adaptation” [16]. Due to their lipophilic nature corticosteroids readily enter the brain and either bind to membrane receptors [42] or freely cross neuronal cell membranes to bind to specific cytoplasmatic receptors [43]. Consequently, corticosteroids may alter neural activity rapidly by modulation of ion channels and second-messenger systems [42] and by receptor-mediated protein-protein interactions [44] or, more slowly by receptor-mediated, long-lasting genomic actions [45]. Through the latter mechanism, corticosteroids may lead to altered transcription of specific genes resulting in changes in protein synthesis and, consequently, in the regulation of enzymes, neurotransmitters and receptors [45], [46].
In neurons, corticosteroids may bind to two dramatically different intracellular receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) [47], [48]. Interestingly, the MRs and GRs are co-located in those brain structures that are involved in the regulation of fear and anxiety, such as hippocampus, septum, and amygdala [48], [49], [50], [51], [52], [53]. GRs are also distributed in other parts of the brain and the highest concentrations are found in regions involved in feedback regulation of the hormonal stress response, for example paraventricular hypothalamus, hippocampus and pituitary [48], [54], [55], [56], [57]. The two receptor types not only differ in their neuroanatomical distribution, but also in their affinity and binding capacity for corticosteroids [48].
MRs have a high affinity for corticosterone and aldosterone and are almost saturated under basal conditions. In contrast, GRs have a 10-fold lower affinity for corticosterone than MRs and become occupied only during stress and at the circadian peak, when glucocorticoids are high [19], [48], [58]. Furthermore, the numbers of hippocampal MRs display a circadian rhythm, whereas the GR system does not [59]. Therefore, it is postulated that in healthy organisms GR action is mainly regulated by the hormone level while MR action is influenced more by receptor density. Thus, in the course of normal diurnal variation when their permissive (tonic) effects predominate, corticosteroids ‘prime’ the stress responses via MRs, and bring them to peaks of readiness for the activities of the day (proactive mode) while, through their suppressive actions via GRs, they prevent the stress reactions from overshooting (reactive mode) [19], [59], [60]. Thus, corticosteroids can play an important role in the maintenance of homeostatic equilibrium via its two receptor types [19], [61].
As a result of the above mentioned differences in MR and GR affinity it is postulated that the same steroid hormone may have different actions on fear and anxiety depending on the phase of the hormonal stress response (before, during or after the rise and peak) and consequent changes in receptor occupation. Therefore, in the experiments reviewed here, special attention was given to the time when MR and/or GR occupation was manipulated (before, during or after stressor exposure) in relation to that of behavioral testing.
Different approaches have been used to manipulate receptor occupancy. In adrenalectomized (ADX) animals circulating corticosteroids are absent [62] and replacement with corticosterone is often used to show that it can combat the ADX induced effects, thereby indicating its crucial role [62], [63]. The effects of corticosterone on emotional behavior are dose dependent and reflect differential receptor occupancy. For example, in rats 30 μg corticosterone/100 g body weight results in full occupancy of MRs and about 25% occupancy of GRs, whereas about 75% occupancy of GRs can be observed after a dose of 300 μg [47], [57], [59], [64]. It is important to realize that ADX-rats have higher pain thresholds from the 2nd to 6th postoperative days than sham-operated animals [65]. That is one of the reasons why, in many of the studies presented here, rats were ADX 24 h after the administration of an aversive stimulus (e.g. footshock) and 1 h before behavioral testing. Adrenomedullectomized (ADMX) animals are sometimes used as a negative control because corticosterone can still be released from the adrenal cortex, but, since the medulla has been removed, there are no circulating catecholamines of adrenal origin [64]. Metyrapone, an 11-beta-hydroxylase inhibitor, is often used as an alternative for ADX because it is a powerful and selective blocker of corticosteroid synthesis and thereby produces a kind of partial chemical adrenalectomy [66]. Behavioral effects are again dose dependent; because a low dose of metyrapone, e.g. 25 mg/kg injected subcutaneously predominantly blocks GR-mediated responses whereas a higher dose (50 mg) impairs both MR- and GR-mediated processes [67]. Synthetic steroids such as RU28362 (GR agonist), RU38486 (GR antagonist) and RU28318 or spironolactone (MR antagonists) are very useful tools for manipulating the receptors [68], [69]. The peripheral use of the glucocorticoid dexamethasone DEX in behavioral studies is not extensively reviewed here because, in contrast to corticosterone, it shows poor penetration of the brain [70]. Transgenic mice in which GR receptor function has been impaired by partial ‘knock-out’ of the genes encoding for GR proteins provide a chronic model for studying GR function [71]. The use of antisense segments, that pair with the GRmRNA or MRmRNA preventing the synthesis of protein from the mRNA, is another modern tool investigating corticosteroid receptor involvement in specific brain areas [72], [73].
Section snippets
The ontogeny of freezing behavior
The ontogeny of freezing behavior has mainly been studied by Takahashi and co-workers [74], [75]. In the rat, freezing behavior first appears near the end of the second postnatal week. It can be induced by removing the pup from the nest at 14 days of age and exposing it to an unfamiliar anesthetized adult male rat for 10 min, but not to the nursing dam, a familiar adult male rat, or a juvenile [76]. It was suggested that the expression of this freezing behavior required a combination of
Different corticosteroid receptor mechanisms involved in different aspects of fear and anxiety
Fig. 1 summarizes the actions of corticosteroids on fear and anxiety. These actions are highly dependent on whether the stressor is unconditioned or conditioned as well as on the phase of the corticosteroid stress response (before, during or after exposure to the stressor) that determines occupation of GRs and/or MRs. Corticosteroids are involved in the following aspects of fear and anxiety.
- (a)
Unconditioned fear (acute). At relatively low levels of corticosterone, the hormone exerts a
Conclusion
Under healthy conditions, corticosteroids mediate behavioral adaptation via central MR and GR-mechanisms. Here I speculate about the corticosteroid mechanisms, obtained from laboratory experiments, and their adapative role in a natural environment.
Animals immediately freeze and remain alert when a predator or other source of danger is detected thereby reducing the likelihood of detection and attack from a predator. This behavioral response can already be observed before the HPA axis is actived.
Acknowledgements
I thank Drs Bryan Jones and Bauke Buwalda for helpful criticism of the manuscript. While this paper was being reviewed, Professor Béla Bohus passed away unexpectedly on 19 September 2000 at the age of 64. Béla had been a mentor, a friend and a source of inspiration to me, for the past 11 years, I had the privilege to work with him. Therefore, I would like to dedicate this review to his memory.
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