Elsevier

Biological Psychiatry

Volume 55, Issue 4, 15 February 2004, Pages 367-375
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2003.10.007Get rights and content

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.

Section snippets

Animals

Animal studies were approved by the Emory University Institutional Care and Use Committee under National Institutes of Health (NIH) Guidelines for the Care and Use of Laboratory Animals. Timed-pregnant Long Evans Crl:(LE)BR rats (Charles River Laboratories, Portage, Michigan) arrived at Emory University on gestation days 11 to 12. All dams were housed in transparent, polypropylene cages containing 2 cm of wood shaving bedding. Animals had ad libitum access to food (Purina Lab Chow) and water in

Plasma ACTH

Two-way ANOVA with repeated measures on time revealed significant effects for both rearing [F(1,8) = 13.4, p < .01) and time [F(6,48) = 2.39, p < .05) on serial plasma ACTH concentrations following acute APS (Figure 1). Although there were no rearing effects for basal am ACTH concentration, we observed marked rearing differences in peak ACTH responses and time of recovery. In HMS15 animals, plasma ACTH concentrations peaked 5 minutes after stressor presentation and quickly declined toward

Discussion

In this study, we report persistent molecular and functional adaptations in central corticosteroid receptors following moderate versus brief handling-maternal separation (HMS) in Long Evans Hooded rats. Previous neuroendocrine studies have shown little difference between rats reared under normal animal facility care and the HMS15 condition (Ladd et al 2000, Plotsky and Meaney 1993), which represents a handling and cage transfer control. Therefore, we did not include a separate animal facility

Acknowledgements

This study was funded by National Institutes of Health Grants MH50113 (PMP) and MH12163 (COL) and the Emory University Silvio O. Conte Center for the Neuroscience of Mental Disease (MH58922).

CBN has received grants from Abbott Laboratories, American Foundation for Suicide Prevention, AstraZeneca, Bristol-Myers-Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck, National Alliance for Research on Schizophrenia and Depression, National Institute of Mental Health,

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