Perinatal Food Deprivation Induces Marked Alterations of the Hypothalamo-Pituitary-Adrenal Axis in 8-Month-Old Male Rats both under Basal Conditions and after a Dehydration Period

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Abstract

Dehydration is a classic homeostatic stressor in rats that leads to a series of endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. During the last decade, it has been well established that perinatal food restriction is associated with the onset of diseases in adults. Our previous demonstration of long-term alterations in HPA axis activity in both basal conditions and after a 72-hour dehydration period in 4-month-old rats exposed to a 50% maternal food restriction (FR50) in late gestation and lactation prompted us to investigate whether such perinatal undernutrition further affects HPA axis activity in mature animals. As previously described in 4-month-old rats under basal conditions, 8-month-old FR50 rats showed reduced body weight and an enhanced ratio between mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA levels in the hippocampus, as well as increased pro-opiomelanocortin (POMC) mRNA levels in the adenohypophysis. In addition, numerous additional alterations appeared in mature rats. In the hypothalamus, levels of vasopressin (VP) mRNAs were increased both in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). In the adenohypophysis, GR and prohormone-convertase 2 (PC2) mRNA levels were significantly increased, whereas prohormone-convertase 1 (PC1) mRNA was not affected by maternal undernutrition. Interestingly, undernourished animals exhibited high plasma levels of total and free corticosterone in spite of normal corticotropin (ACTH) levels, an indication that HPA basal activity is enhanced by maternal undernutrition in 8-month-old animals. Dehydration for 72 h induced a rise in ACTH plasma levels, but did not modify total and free corticosterone plasma levels in 8-month-old FR50 animals. In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected. The present study indicates that maternal food restriction during the perinatal period dramatically affects the activity of the HPA axis until the age of 8 months. We speculate that higher basal HPA activity and an inadequate HPA response after dehydration in mature animals may contribute to diseases such as hypertension, known to develop with aging in perinatally growth-restricted rats.

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Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders.

Guy Griebel, Jacques Simiand, Claudine Serradeil-Le Gal … (2002)

The limbic localization of the arginine vasopressin V(1b) receptor has prompted speculation as to a potential role of this receptor in the control of emotional processes. To investigate this possibility, we have studied the behavioral effects of SSR149415, the first selective and orally active non-peptide antagonist of vasopressin V(1b) receptors, in a variety of classical (punished drinking, elevated plus-maze, and light/dark tests) and atypical (fear/anxiety defense test battery and social defeat-induced anxiety) rodent models of anxiety, and in two models of depression [forced swimming and chronic mild stress (CMS)]. When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like activity at doses that ranged from 1 to 30 mg/kg (i.p. or p.o.), but the magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam, which was used as a positive control. In contrast, SSR149415 produced clear-cut anxiolytic-like activity in models involving traumatic stress exposure, such as the social defeat paradigm and the defense test battery (1-30 mg/kg, p.o.). In the forced swimming test, SSR149415 (10-30 mg/kg, p.o.) produced antidepressant-like effects in both normal and hypophysectomized rats. Moreover, in the CMS model in mice, repeated administration of SSR149415 (10 and 30 mg/kg, i.p.) for 39 days improved the degradation of the physical state, anxiety, despair, and the loss of coping behavior produced by stress. These findings point to a role for vasopressin in the modulation of emotional processes via the V(1b) receptor, and suggest that its blockade may represent a novel avenue for the treatment of affective disorders.

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Regulation of pituitary ACTH secretion during chronic stress.

G. Mora-Aguilera (1994)

Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.

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Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.

Chunling Zhang, Raymond Carroll, Virginie Laurent … (2002)

The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1/3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1/3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. They lack mature GHRH, have low pituitary growth hormone (GH) and hepatic insulin-like growth factor-1 mRNA levels and resemble phenotypically the "little" mouse (Gaylinn, B. D., Dealmeida, V. I., Lyons, C. E., Jr., Wu, K. C., Mayo, K. E. & Thorner, M. O. (1999) Endocrinology 140, 5066-5074) that has a mutant GHRH receptor. Despite a severe defect in pituitary proopiomelanocortin processing to mature adrenocorticotropic hormone, blood corticosterone levels are essentially normal. There is marked hyperproinsulinemia but without impairment of glucose tolerance. In contrast, PC2-null mice lack mature glucagon and are chronically hypoglycemic (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc. Natl. Acad. Sci. USA 94, 6646-6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase.

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Author and article information

Journal

Journal ID (publisher-id): NEN

Journal ID (nlm-ta): Neuroendocrinology

Journal ID (doi): 10.1159/issn.0028-3835

Title: Neuroendocrinology

Publisher: S. Karger AG

ISSN (Print): 0028-3835

ISSN (Electronic): 1423-0194

Publication date Subscription-year: 2004

Publication date (Print): May 2004

Publication date (Electronic): 10 June 2004

Volume: 79

Issue: 4

Pages: 163-173

Affiliations

^aLaboratoire de Neuroendocrinologie du Développement, UPRES-EA 2701, Université de Lille 1, Villeneuve-d’Ascq, France; ^bLaboratoire de Physiologie Animale, Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar El Mehrez-Fés, Fés-Atlas, Morocco

Article

Publisher ID: 78098 Other ID: Neuroendocrinology 2004;79:163–173

DOI: 10.1159/000078098

PubMed ID: 15153750

SO-VID: 83231305-f371-46f1-ae48-06f38c4a0bd5

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 06 November 2003

Date accepted : 11 March 2004

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Figures: 4, Tables: 2, References: 63, Pages: 11

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Perinatal Food Deprivation Induces Marked Alterations of the Hypothalamo-Pituitary-Adrenal Axis in 8-Month-Old Male Rats both under Basal Conditions and after a Dehydration Period

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Most cited references 18

Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders.

Regulation of pituitary ACTH secretion during chronic stress.

Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.

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Cited by 9

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