Adaptation of the hypothalamus–pituitary–adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective

doi:10.1016/j.neubiorev.2015.06.013

Neuroscience & Biobehavioral Reviews

Volume 56, September 2015, Pages 35-49

https://doi.org/10.1016/j.neubiorev.2015.06.013 Get rights and content

Highlights

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Reduced HPA response to daily repeated stress is not an habituation-like phenomenon.
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Nearly maximal HPA adaptation is found with one single exposure to severe stressors.
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The stronger the stressor the greater the maximal the adaptation of the HPA response.
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The longer the inter-stress interval the greater the adaptation of the HPA response.
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HPA adaptation to repeated stress might depend on the elaboration of safety signal.

Abstract

Repeated exposure to a wide range of stressors differing in nature and intensity results in a reduced response of prototypical stress markers (i.e. plasma levels of ACTH and adrenaline) after an acute challenge with the same (homotypic) stressor. This reduction has been considered to be a habituation-like phenomenon. However, direct experimental evidence for this assumption is scarce. In the present work we demonstrate in adult male rats that adaptation of the hypothalamus–pituitary–adrenal (HPA) axis to repeated stress does not follow some of the critical rules of habituation. Briefly, adaptation was stronger and faster with more severe stressors, maximally observed even with a single exposure to severe stressors, extremely long-lasting, negatively related to the interval between the exposures and positively related to the length of daily exposure. We offer a new theoretical view to explain adaptation to daily repeated stress.

Section snippets

Adaptation to repeated stress as a habituation process, evidences and contradictions

Exposure to different types of stressors results in a wide range of physiological and behavioral responses, some of them related to the particular nature of the stressor. Activation of the hypothalamus–pituitary–adrenal (HPA) axis constitutes one of the prototypical responses to all kind of stressors. The HPA axis, along with a few set of other physiological responses (i.e. plasma levels of prolactin, adrenaline and glucose) appear to be good markers of the intensity of emotional or

Animals and general procedures

Adult male Sprague–Dawley rats obtained from the breeding centre of the Universitat Autònoma de Barcelona were used. Rats were maintained under standard animal housing conditions (21 °C, 55% to 65% humidity, and a 12-h light/dark cycle: 8 am–8 pm). Rats were housed in pairs and food and water were available at libitum. The experimental protocols were approved by the Committee of Ethics of the Universitat Autònoma de Barcelona and Generalitat de Catalunya, and were carried out in accordance to

Does the response progressively decrease with the number of exposures to the stimulus? (Characteristic number 1)

This criterion predicts that the HPA axis response will decrease with daily repeated exposure to the same stressor to an asymptotic level. To directly test this hypothesis, animals were assigned to either chronic or acute IMO groups. Those assigned to the chronic IMO group were daily exposed to 1 h of IMO for 7 days and the HPA response was followed in the same animals on days 1, 2 and 7. Those assigned to the acute IMO group were only blood sampled on days 1 and 2, but only exposed to 1 h of IMO

General discussion

The present work presents evidence strongly arguing against the consideration of the reduced HPA response to a daily repeated stressor as a habituation-like phenomenon. We propose that the denomination of the process of adaptation to daily repeated stress should change and one possibility is to define it as tolerance. This name can apply to both physical and psychological stressors and does not require to perfectly fit to very specific rules.

The present results suggest that exposure to an

Conclusions

In conclusion, the present set of experiments indicate that the rules defining adaptation of the HPA axis after previous experience with the homotypic stressor do not fit with the concept of habituation. Adaptation is likely to be a learning-like process with particular characteristics not conforming previously accepted types of learning. The present results, by demonstrating that a single exposure to a severe stressor is, under certain conditions, enough to induce maximum HPA adaptation will

Acknowledgements

The laboratory was supported by Spanish grants to AA and/or RN from Ministerio de Economía y Competitividad (SAF2011-28313), Plan Nacional sobre Drogas (2011/021), Instituto de Salud Carlos III (RD12/0028/0014, Redes Temáticas de Investigación Cooperativa en Salud, Ministerio de Sanidad y Consumo), and Generalitat de Catalunya (SGR2014-1020). Silvia Fuentes was a recipient of a PTA-MICINN fellowship (PTA 2010-3472-I). Roser Nadal is a recipient of an ICREA Academia fellowship (Generalitat de

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Citation Excerpt :
It is unlikely that the lower ACTH levels after SWIM than IMO reflects a greater negative glucocorticoid feedback rather than a lower intensity of the former stressor. When comparing both, the impact of IMO in terms of the post-stress recovery time, impact on food intake in the next 24 h and heterotypic HPA sensitization is stronger (Belda et al., 2016; Rabasa et al., 2015). To avoid carry over effects of prior exposure to other stressors, we exposed the animals first to presumably low intensity stressors (OF1, EP), then to SWIM and finally to the most severe stressor (IMO).
Biological response to stressors is critical to understand stress-related pathologies and vulnerability to psychiatric diseases. It is assumed that we can identify trait-like characteristics in biological responsiveness by testing subjects in a particular stressful situation, but there is scarce information on this issue. We then studied, in a normal outbred population of adult male rats (n = 32), the response of well-characterized stress markers (ACTH, corticosterone and prolactin) to different types of stressors: two novel environments (open-field, OF1 and OF2), an elevated platform (EP), forced swim (SWIM) and immobilization (IMO). Based on both plasma ACTH and prolactin levels, the OF1 was the lowest intensity situation, followed by the OF2 and the EP, then SWIM and finally IMO. When correlations between the individual responses to the different stressors were studied, the magnitude of the correlations was most dependent on the similarities in intensity rather than on other characteristics of stressors, with good correlations between similar intensity stressors and no correlations at all were found between stressors markedly differing in intensity. In two additional confirmatory experiments (n = 37 and n = 20) with HPA hormones, we observed good correlation between the response to restraint and IMO, which were close in intensity, and no correlation between OF1 and SWIM. The present results suggest that individual neuroendocrine response to a particular stressor does not predict the response to another stressor greatly differing in intensity, thus precluding characterization of low or high responsive individuals to any stressor in a normal population. The present data have important implications for human studies.
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The extant literature predicts that initial hypothalamic-pituitary-adrenocortical (HPA) axis response magnitude and subsequent habituation are associated with health, such that both heightened stress reactivity and non-habituation to repeated stressors are associated with disease. Yet, despite evidence for an association between initial HPA axis reactivity and subsequent habituation, the extant literature often considers health implications of these stress response patterns independently or make interpretations based on an initial response alone. This may be because past tests of the association between reactivity and habituation were subject to statistical bias (e.g., regression to the mean), and no prior work has examined the association between initial cortisol reactivity and subsequent habituation using analytic strategies capable of estimating the unbiased relationship between initial value (i.e., reactivity) and subsequent change (i.e., habituation). Accordingly, the present investigation drew from two previously published studies to test the association between initial HPA axis reactivity and subsequent habituation using analytic strategies capable of estimating the relationship between initial reactivity and subsequent habituation with minimal bias.
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As predicted, results indicated a negative relationship (Pearson’s r ranging from -0.27 to -0.91) where initial HPA axis reactivity was associated with subsequent habituation across both studies, even when using estimation procedures capable of producing an unbiased estimate of this relationship.
Results support the claim that initial HPA axis reactivity to acute stress is associated with subsequent habituation, such that initially high reactors are likely to habituate, whereas initially blunted reactors are likely to sensitize. In view of these results, hypothesized long-term health implications of acute cortisol reactivity and habituation patterns should be considered in tandem.

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¹: Present address: Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

View full text

ReviewAdaptation of the hypothalamus–pituitary–adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective

Highlights

Abstract

Section snippets

Adaptation to repeated stress as a habituation process, evidences and contradictions

Animals and general procedures

Does the response progressively decrease with the number of exposures to the stimulus? (Characteristic number 1)

General discussion

Conclusions

Acknowledgements

Psychoneuroendocrinology

Horm Behav.

Horm Behav.

Behav. Brain Res.

Trends Endocrinol. Metab.

Pharmacol. Biochem. Behav.

Neuroscience

Biol. Psychiatry

Neuroscience

Behav. Brain Res.

Psychoneuroendocrinology

Brain Res.

Physiol. Behav.

Behav. Brain Res.

Neuroscience

Neuroscience

Horm Behav.

Front Neuroendocrinol.

Brain Behav. Immun.

Psychoneuroendocrinology

Brain Res.

Neuroscience

Int. J. Dev. Neurosci.

Brain Res.

Physiol. Behav.

Physiol. Behav.

Psychoneuroendocrinology

Biol. Psychiatry

Behav. Brain Res.

Neurobiol. Learn. Mem.

Domest. Anim. Endocrinol.

Neurobiol. Learn. Mem.

Brain Behav. Immun.

Neuroscience

Studying chronic stress in animals: purposes, models and consequences

The hypothalamic–pituitary–adrenal axis: what can it tell us about stressors?

CNS Neurol. Disord. Drug Targets

What can we know from pituitary–adrenal hormones about the nature and consequences of exposure to emotional stressors?

Cell. Mol. Neurobiol.

Evidence that the pituitary–adrenal axis does not cross-adapt to stressors: comparison to other physiological variables

Neuroendocrinology

A single exposure to severe stressors causes long-term desensitisation of the physiological response to the homotypic stressor

Stress

Adaptation in the corticosterone and hyperthermic responses to stress following repeated stressor exposure

J. Neuroendocrinol.

Lesions of the posterior paraventricular thalamus block habituation of hypothalamic–pituitary–adrenal responses to repeated restraint

J. Neuroendocrinol.

Changes in hypothalamic–pituitary–adrenal function, body temperature, body weight and food intake with repeated social stress exposure in rats

J. Neuroendocrinol.

The sensory insular cortex mediates the stress-buffering effects of safety signals but not behavioral control

J. Neurosci.

Inhibition of fear by learned safety signals: a mini-symposium review

J. Neurosci.

Review
Adaptation of the hypothalamus–pituitary–adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective