Hypothalamic-pituitary-adrenal function in chronic intermittently cold-stressed neonatally handled and non handled rats

J Neuroendocrinol. 1995 Feb;7(2):97-108. doi: 10.1111/j.1365-2826.1995.tb00672.x.


Neonatally handled (H) animals, as adults, exhibit lower ACTH and corticosterone (B) responses to a number of acute stressors compared to their non-handled (NH) counterparts. However, little is known about activity within the hypothalamic-pituitary-adrenal (HPA) axis of H and NH animals under conditions of chronic stress. We, therefore, examined HPA function in adult H and NH rats exposed to chronic intermittent cold stress (4 h of 4 degrees C cold a day for 21 days; H CHR and NH CHR) and in control H and NH (H CTL and NH CTL) rats. H CTL and NH CTL animals displayed comparable ACTH and B responses to a single, acute exposure to cold. We found that H CHR animals exhibited lower levels of ACTH, but not B, during the 21st exposure to cold (the homotypic stressor) compared to the first exposure to cold in H CTL; however, ACTH and B levels in NH CHR were not different from those in NH CTL. In contrast, NH CHR animals hypersecreted ACTH and B in response to restraint (the novel, heterotypic stressor) compared to NH CTL and both H groups, whereas H CHR and H CTL animals did not differ in their responses to restraint. These endocrine responses were associated with increased basal median eminence levels of both CRH and AVP in H CHR and NH CHR relative to their control groups (with NH CHR exhibiting the highest absolute levels of each secretagogue), and with decreased glucocorticoid receptor densities in septum of both H CHR and NH CHR. In addition, the expected lower glucocorticoid receptor density in hippocampus and frontal cortex of NH rats compared to H rats was observed. We believe that the difference in glucocorticoid receptor density between H and NH animals in the hippocampus and frontal cortex and the associated differences in secretagogue content in the median eminence are related to the hypersecretion of ACTH and B in the NH CHR relative to the other groups. Furthermore, we hypothesize that an active inhibitory process is involved in the adaptation of HPA responses of H CHR animals to the homotypic stressor, and present a working model of regulation of activity within the CRH/AVP neurons in the PVN.

Publication types

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

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Arginine Vasopressin / metabolism
  • Basal Metabolism
  • Chronic Disease
  • Cold Temperature*
  • Corticosterone / metabolism
  • Corticotropin-Releasing Hormone / metabolism
  • Handling, Psychological*
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Male
  • Median Eminence / metabolism
  • Oxytocin / metabolism
  • Pituitary-Adrenal System / physiopathology*
  • Rats
  • Stress, Physiological / physiopathology*


  • Arginine Vasopressin
  • Oxytocin
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Corticosterone