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

• Published in: Biological psychiatry (1969) 2004-02, Vol.55 (4), p.367-375
• Main Authors: Ladd, Charlotte O, Huot, Rebecca L, Thrivikraman, K.V, Nemeroff, Charles B, Plotsky, Paul M
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - genetics; Adaptation, Physiological - physiology; Adrenocorticotropic Hormone - blood; Affectivity. Emotion; Animals; Animals, Newborn; Behavioral psychophysiology; Biological and medical sciences; Corticosterone - blood; Densitometry - methods; dexamethasone; Dexamethasone - pharmacology; Feedback, Physiological; Female; Fundamental and applied biological sciences. Psychology; Glucocorticoid receptor; Glucocorticoids - pharmacology; Hippocampus - metabolism; Hormones and behavior; HPA axis; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; In Situ Hybridization - methods; Male; Maternal Deprivation; maternal separation; mineralocorticoid receptor; Personality. Affectivity; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Pregnancy; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Radioimmunoassay - methods; Rats; Rats, Long-Evans; Receptors, Glucocorticoid - chemistry; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - chemistry; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; RNA, Messenger - metabolism; Time Factors
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2003.10.007

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. 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. 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. 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.