Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation

Charlotte O. Ladd, Rebecca L. Huot, K. V. Thrivikraman, Charles Nemeroff, Paul M. Plotsky

Research output: Contribution to journalArticle

268 Citations (Scopus)

Abstract

Background: Maternally separated rats exhibit exaggerated hypothalamic-pituitary-adrenal responses to an acute stressor but normal diurnal trough functioning. We hypothesized that maternally separated rats experience adequate proactive glucocorticoid negative feedback but deficient "reactive" negative feedback, contributing to prolonged hypothalamic-pituitary-adrenal stress responses. Methods: We measured plasma adrenocorticotropic hormone and corticosterone concentrations following an acute stressor or 6 to 8 hours after dexamethasone administration in adult rats previously exposed to daily handling-maternal separation for 15 minutes (HMS15) or 180 minutes (HMS180) during postnatal days 2 to 14. We also examined regional mineralocorticoid receptor and glucocorticoid receptor messenger RNA density in these two groups. Results: HMS180 rats appeared to escape dexamethasone suppression of plasma adrenocorticotropic hormone and corticosterone faster than their HMS15 counterparts (p < .01). In situ hybridization analysis revealed increased hippocampal mineralocorticoid receptor messenger RNA density (p < .05) with decreased cortical (p < .05) and hippocampal (p < .05) glucocorticoid receptor messenger RNA density in HMS180 versus HMS15 animals. Conclusions: These results are consistent with the hypothesis that in rats exposed to moderate neonatal handling-maternal separation, enhanced proactive feedback maintains the hypothalamic-pituitary- adrenal axis during the diurnal trough, while decreased reactive feedback contributes to prolonged responsiveness of the hypothalamic-pituitary-adrenal axis following an acute stressor.

Original languageEnglish
Pages (from-to)367-375
Number of pages9
JournalBiological Psychiatry
Volume55
Issue number4
DOIs
StatePublished - Feb 15 2004
Externally publishedYes

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Mineralocorticoid Receptors
Glucocorticoid Receptors
Mothers
Messenger RNA
Corticosterone
Adrenocorticotropic Hormone
Dexamethasone
Glucocorticoids
In Situ Hybridization

Keywords

  • Dexamethasone
  • Glucocorticoid receptor
  • HPA axis
  • Maternal separation
  • Mineralocorticoid receptor

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. / Ladd, Charlotte O.; Huot, Rebecca L.; Thrivikraman, K. V.; Nemeroff, Charles; Plotsky, Paul M.

In: Biological Psychiatry, Vol. 55, No. 4, 15.02.2004, p. 367-375.

Research output: Contribution to journalArticle

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AU - Nemeroff, Charles

AU - Plotsky, Paul M.

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AB - Background: Maternally separated rats exhibit exaggerated hypothalamic-pituitary-adrenal responses to an acute stressor but normal diurnal trough functioning. We hypothesized that maternally separated rats experience adequate proactive glucocorticoid negative feedback but deficient "reactive" negative feedback, contributing to prolonged hypothalamic-pituitary-adrenal stress responses. Methods: We measured plasma adrenocorticotropic hormone and corticosterone concentrations following an acute stressor or 6 to 8 hours after dexamethasone administration in adult rats previously exposed to daily handling-maternal separation for 15 minutes (HMS15) or 180 minutes (HMS180) during postnatal days 2 to 14. We also examined regional mineralocorticoid receptor and glucocorticoid receptor messenger RNA density in these two groups. Results: HMS180 rats appeared to escape dexamethasone suppression of plasma adrenocorticotropic hormone and corticosterone faster than their HMS15 counterparts (p < .01). In situ hybridization analysis revealed increased hippocampal mineralocorticoid receptor messenger RNA density (p < .05) with decreased cortical (p < .05) and hippocampal (p < .05) glucocorticoid receptor messenger RNA density in HMS180 versus HMS15 animals. Conclusions: These results are consistent with the hypothesis that in rats exposed to moderate neonatal handling-maternal separation, enhanced proactive feedback maintains the hypothalamic-pituitary- adrenal axis during the diurnal trough, while decreased reactive feedback contributes to prolonged responsiveness of the hypothalamic-pituitary-adrenal axis following an acute stressor.

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