Previous work has indicated that acute and repeated stress can alter thyroid hormone secretion. Corticosterone, the end product of hypothalamic-pituitary-adrenal (HPA) axis activation and strongly regulated by stress, has been suggested to play a role in hypothalamic-pituitary-thyroid (HPT) axis regulation. In the current study, we sought to further characterize HPT axis activity after repeated exposure to inescapable foot-shock stress (FS), and to examine changes in proposed regulators of the HPT axis, including plasma corticosterone and hypothalamic arcuate nucleus agouti-related protein (AGRP) mRNA levels. Adult male Sprague-Dawley rats were subjected to one daily session of inescapable FS for 14 days. Plasma corticosterone levels were determined during and after the stress on days 1 and 14. Animals were killed on day 15, and trunk blood and brains were collected for measurement of hormone and mRNA levels. Repeated exposure to FS led to a significant decrease in serum levels of 3,5,3′-triiodothyronine (T3) and 3,5,3′,5′-tetraiodothyronine (T4). Stress-induced plasma corticosterone levels were not altered by repeated exposure to the stress. Despite the decrease in peripheral hormone levels, thyrotropin-releasing hormone (TRH) mRNA levels within the paraventricular nucleus of the hypothalamus were not altered by the stress paradigm. Arcuate nucleus AGRP mRNA levels were significantly increased in the animals exposed to repeated FS. Additionally, we noted significant correlations between stress-induced plasma corticosterone levels and components of the HPT axis, including TRH mRNA levels and free T4 levels. Additionally, there was a significant correlation between AGRP mRNA levels and total T3 levels. Changes in body weight were also correlated with peripheral corticosterone and TRH mRNA levels. These results suggest that repeated exposure to mild-electric foot-shock causes a decrease in peripheral thyroid hormone levels, and that components of the HPA axis and hypothalamic AGRP may be involved in stress regulation of the HPT.

Keywords:
Thyrotropin-releasing hormone, Adrenal steroids, Paraventricular nucleus of the hypothalamus, Agouti-related protein, Thyroid hormones, Arcuate nucleus, Stress
1.
Baumgartner A: Thyroxine and the treatment of affective disorders: An overview of the results of basic and clinical research. Int J Neuropsychopharmacol 2000;3:149–165.
2.
Joffe R, Segal Z, Singer W: Changes in thyroid hormone levels following response to cognitive therapy for major depression. Am J Psychiatry 1996;153:411–413.
3.
Dellovade T, Zhu YS, Krey L, Pfaff D: Thyroid hormone and estrogen interact to regulate behavior. Proc Natl Acad Sci USA 1996;93:12581–12586.
4.
Crockford S: Thyroid rhythm phenotypes and hominid evolution: A new paradigm implicates pulsatile hormone secretion in speciation and adaptation changes. Comp Biochem Physiol A Mol Integr Physiol 2003;135:105–129.
5.
Lazar M: Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr Rev 1993;14:184–193.
6.
Puymirat J: Thyroid receptors in the rat brain. Prog Neurobiol 1992;39:281–294.
7.
Scanlon M: Endocrine functions of the hypothalamus and alterations in neuroendocrine function – focus on thyrotropin and growth hormone. Prog Brain Res 1992;93:19–30.
8.
Morley J: Neuroendocrine control of thyrotropin secretion. Endocr Rev 1981;2:396–436.
9.
Turakulov Y, Burikhanov R, Pakitdinov P, Myslitskaya A: Influence of immobilization stress on the levels of thyroid hormones. Neurosci Behav Physiol 1994;24:462–464.
10.
Marti O, Gavalda A, Jolin T, Armario A: Acute stress attenuates but does not abolish circadian rhythmicity of serum thyrotropin and growth hormone in the rat. Eur J Endocrinol 1996;135:703–708.
11.
Langer P, Foldes O, Kvetnansky R, Culman J, Torda T, El Daher F: Pituitary-thyroid function during acute immobilization stress in rats. Exp Clin Endocrinol 1983;82:51–60.
12.
Cizza G, Brady L, Escpales M, Blackman M, Gold P, Chrousus G: Age and gender influence basal and stress-modulated hypothalamic-pituitary-thyroidal function in Fisher 344/N rats. Neuroendocrinology 1996;64:440–448.
13.
Armario A, Castellanos J, Balasch J: Effect of acute and chronic psychogenic stress on corticoadrenal and pituitary-thyroid hormones in male rats. Horm Res 1984;20:241–245.
14.
Kondo K, Harbuz M, Levy A, Lightman S: Inhibition of the hypothalamic-pituitary-thyroid axis in response to lipopolysaccharide is independent of changes in circulating corticosteroids. Neuroimmunomodulation 1997;4:188–194.
15.
Servatius R, Natelson B, Moldow R, Pogach L, Brennan F, Ottenweller J: Persistent neuroendocrine changes in multiple hormonal axes after a single or repeated stressor exposures. Stress 2000;3:263–274.
16.
Van Haasteren G, Linkels E, Klootwijk W, van Toor H, Rondeel J, Themmen A, de Jong F, Valentijn K, Vaudry H, Bauer K, Visser T, de Greef W: Starvation-induced changes in the hypothalamic content of prothyrotropin-releasing hormone (proTRH) mRNA and the hypothalamic release of proTRH-derived peptides: role of the adrenal gland. J Endocrinol 1995;145:143–153.
17.
Fekete C, Legradi G, Mihaly E, Huang QH, Tatro J, Rand W, Emerson C, Lechan R: α-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J Neurosci 2000;20:1550–1558.
18.
Keller-Wood M, Dallman M: Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5:1–24.
19.
Kakucksa I, Qi Y, Lechan R: Changes in adrenal status affect hypothalamic thyrotropin-releasing hormone gene expression in parallel with corticotropin-releasing hormone. Endocrinology 1995;136:2795–2802.
20.
Bianco A, Nunes M, Hell N, Maciel R: The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3,5,3′-triiodothyronine generation in rats. Endocrinology 1987;120:1033–1038.
21.
Luo LG, Bruhn T, Jackson I: Glucocorticoids stimulate thyrotropin-releasing hormone gene expression in cultured hypothalamic neurons. Endocrinology 1995;136:4945–4950.
22.
Ahlquist J, Franklyn J, Ramsden D, Sheppard M: The influence of dexamethasone on serum thyrotrophin and thyrotropin synthesis in the rat. Mol Cell Endocrinol 1989;64:55–61.
23.
Shi ZX, Levy A, Lightman S: Thyroid hormone-mediated regulation of corticotropin-releasing hormone messenger ribonucleic acid in the rat. Endocrinology 1994;134:1577–1580.
24.
Nolan L, Windle R, Wood S, Kershaw Y, Lunness H, Lightman S, Ingram C, Levy A: Chronic iodine deprivation attentuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats. J Neuroendocrinol 2000;12:1149–1159.
25.
Tohei A, Watanabe G, Taya K: Hypersecretion of corticotrophin-releasing hormone and arginine vasopressin in hypothyroid male rats as estimated with push-pull perfusion. J Endocrinol 1998;156:395–400.
26.
Redei E, Hilderbrand H, Aird F: Corticotropin release inhibiting factor is encoded within prepro-TRH. Endocrinology 1995;136:1813–1816.
27.
Fekete C, Sarkar S, Rand W, Harney J, Emerson C, Bianco A, Lechan R: Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis: Comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPT axis. Endocrinology 2002;143:3846–3853.
28.
Sarkar S, Lechan R: Central administration of neuropeptide Y reduces α-melanocyte-stimulating hormone-induced cyclic adenosine 5′-monophosphate response element binding protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 2003;144:281–291.
29.
Small C, Kim M, Stanley S, Mitchell J, Murphy K, Morgan D, Ghatei M, Bloom S: Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals. Diabetes 2001;50:248–254.
30.
Schafer KH, Herman J, Watson S: In situ hybridization histochemistry; in London E (ed): Imaging Drug Action in the Brain. Boca Raton, CRC Press, 1993, pp 337–377.
31.
Swanson L: Brain Maps: Structure of the Rat Brain, ed 2. New York, Elsevier, 1998.
32.
Howell D: Statistical Methods for Psychology. Boston, PWS Publishers, 1982.
33.
Helmreich D, Crouch M, Parfitt D: Thyroid hormone levels during controllable and non-controllable stress; in 2001 Abstract Viewer/Intinerary Planner. Washington, Society for Neuroscience, 2001, p 732.7.
34.
Silberman D, Wald M, Genaro A: Effects of chronic mild stress on lymphocyte proliferative response. Participation of serum thyroid hormones and corticosterone. Int Immunopharmacol 2002;2:487–497.
35.
Yen YM, Distefano JI, Yamada H, Nguyen T: Direct measurement of whole body thyroid hormone pool sizes and interconversion rates in fasted rats: Hormone regulation implications. Endocrinology 1994;134:1700–1709.
36.
Kant G, Eggleston T, Landman-Roberts L, Kenion C, Driver G, Meyerhoff J: Habituation to repeated stress is stressor specific. Pharmacol Behav 1985;22:631–634.
37.
Dallman M, Pecoraro N, Akana S, la Fleur S, Gomez F, Houshyar H, Bell M, Bhatnagar S, Laugero K, Manalo S: Chronic stress and obesity: A new view of ‘comfort’ food. Proc Natl Acad Sci USA 2003;100:11696–11701.
38.
Helmreich D, Morano M, Akil H, Watson S: Correlation between changes in stress-induced corticosterone secretion and GR mRNA levels. Stress 1997;2:101–112.
© 2005 S. Karger AG, Basel
2005
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.