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Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone.
Neuroendocrinology 2002; 76(3):158-69N

Abstract

We studied the long-term effect of neonatal treatment with the synthetic glucocorticoid dexamethasone (DEX) on stress responsivity later in life. It was found that the plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) responses induced by novelty or conditioned fear stress were markedly attenuated in adult rats that had been neonatally treated with DEX as compared with saline (SAL)-treated controls. Since there were no differences in the heart rate, body temperature, plasma noradrenaline, plasma adrenaline and behavioral responses to these stressors, this points to a deficit within the hypothalamic-pituitary-adrenal (HPA) axis of DEX rats. We found no differences between DEX and SAL rats in basal plasma CORT concentrations measured throughout the circadian cycle, nor in the fraction unbound of CORT circulating under resting conditions, indicating normal tonic regulation of the HPA axis in DEX rats. Since we also found no differences in the hormonal responses induced by intravenous injection of graded doses of ACTH or corticotropin-releasing hormone (CRH), we investigated the sensitivity of the HPA response to stress for inhibition by glucocorticoids. Pretreatment with a low dose of CORT that did not affect the HPA response of SAL rats markedly inhibited the ACTH and CORT responses induced by novelty stress in DEX rats. This strongly suggests that an enhanced corticosteroid feedback underlies the blunted HPA response to stress in DEX rats. Finally, using quantitative immunocytochemistry, we found an increase in arginine-vasopressin (AVP) but not CRH stores in the external zone of the median eminence, suggesting an altered AVP/CRH ratio in the secretory output of the hypophysiotropic paraventricular nucleus. Taken together, our results show that exposure to DEX during early life leads to hyporesponsivity of the HPA axis to stress most likely due to hypersensitivity of the axis for negative feedback by corticosteroids at the suprapituitary level.

Authors+Show Affiliations

Department of Pharmacology and Anatomy, Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12218348

Citation

Kamphuis, Patrick J G H., et al. "Enhanced Glucocorticoid Feedback Inhibition of Hypothalamo-pituitary-adrenal Responses to Stress in Adult Rats Neonatally Treated With Dexamethasone." Neuroendocrinology, vol. 76, no. 3, 2002, pp. 158-69.
Kamphuis PJ, Bakker JM, Broekhoven MH, et al. Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone. Neuroendocrinology. 2002;76(3):158-69.
Kamphuis, P. J., Bakker, J. M., Broekhoven, M. H., Kunne, C., Croiset, G., Lentjes, E. G., ... Wiegant, V. M. (2002). Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone. Neuroendocrinology, 76(3), pp. 158-69.
Kamphuis PJ, et al. Enhanced Glucocorticoid Feedback Inhibition of Hypothalamo-pituitary-adrenal Responses to Stress in Adult Rats Neonatally Treated With Dexamethasone. Neuroendocrinology. 2002;76(3):158-69. PubMed PMID: 12218348.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone. AU - Kamphuis,Patrick J G H, AU - Bakker,Joost M, AU - Broekhoven,Mark H, AU - Kunne,Cindy, AU - Croiset,Gerda, AU - Lentjes,Eef G, AU - Tilders,Fred J H, AU - van Bel,Frank, AU - Wiegant,Victor M, PY - 2002/9/10/pubmed PY - 2002/10/10/medline PY - 2002/9/10/entrez SP - 158 EP - 69 JF - Neuroendocrinology JO - Neuroendocrinology VL - 76 IS - 3 N2 - We studied the long-term effect of neonatal treatment with the synthetic glucocorticoid dexamethasone (DEX) on stress responsivity later in life. It was found that the plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) responses induced by novelty or conditioned fear stress were markedly attenuated in adult rats that had been neonatally treated with DEX as compared with saline (SAL)-treated controls. Since there were no differences in the heart rate, body temperature, plasma noradrenaline, plasma adrenaline and behavioral responses to these stressors, this points to a deficit within the hypothalamic-pituitary-adrenal (HPA) axis of DEX rats. We found no differences between DEX and SAL rats in basal plasma CORT concentrations measured throughout the circadian cycle, nor in the fraction unbound of CORT circulating under resting conditions, indicating normal tonic regulation of the HPA axis in DEX rats. Since we also found no differences in the hormonal responses induced by intravenous injection of graded doses of ACTH or corticotropin-releasing hormone (CRH), we investigated the sensitivity of the HPA response to stress for inhibition by glucocorticoids. Pretreatment with a low dose of CORT that did not affect the HPA response of SAL rats markedly inhibited the ACTH and CORT responses induced by novelty stress in DEX rats. This strongly suggests that an enhanced corticosteroid feedback underlies the blunted HPA response to stress in DEX rats. Finally, using quantitative immunocytochemistry, we found an increase in arginine-vasopressin (AVP) but not CRH stores in the external zone of the median eminence, suggesting an altered AVP/CRH ratio in the secretory output of the hypophysiotropic paraventricular nucleus. Taken together, our results show that exposure to DEX during early life leads to hyporesponsivity of the HPA axis to stress most likely due to hypersensitivity of the axis for negative feedback by corticosteroids at the suprapituitary level. SN - 0028-3835 UR - https://www.unboundmedicine.com/medline/citation/12218348/Enhanced_glucocorticoid_feedback_inhibition_of_hypothalamo_pituitary_adrenal_responses_to_stress_in_adult_rats_neonatally_treated_with_dexamethasone_ L2 - https://www.karger.com?DOI=10.1159/000064526 DB - PRIME DP - Unbound Medicine ER -