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

Neurosci Biobehav Rev. 2015 Sep;56:35-49. doi: 10.1016/j.neubiorev.2015.06.013. Epub 2015 Jun 22.


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.

Keywords: ACTH; Corticosterone; Habituation; Immobilization; Repeated stress; Restraint; Water stress; c-fos.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptation, Physiological / physiology*
  • Animals
  • Habituation, Psychophysiologic*
  • Humans
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Pituitary-Adrenal System / physiopathology*
  • Stress, Psychological* / pathology
  • Stress, Psychological* / physiopathology
  • Stress, Psychological* / psychology