Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis stimulates the release of both facilitatory and inhibitory components. We proposed that the transient removal of the inhibitory component, corticosterone, during a stressor would leave the HPA axis in a state of hyper-responsiveness (facilitated state). Consistent with this expectation, we have previously observed that aminoglutethimide (AG)-induced removal of corticosterone during an immobilization stressor resulted in the hypersecretion of both ACTH and corticosterone to a subsequent stressor. In the present study we determined the effect of stressor duration on the magnitude of facilitation. AG plus a 10-min immobilization (IMM10) stress on day 1 resulted in facilitation of the HPA axis. This was reflected in higher ACTH and corticosterone responses to an injection stress on day 2 as compared to appropriate control rats. AG plus a 60-min immobilization (IMM60) stress on day 1 resulted in significantly greater facilitation as compared to the AG+IMM10 pretreatment. It is apparent that facilitation of the HPA axis is dependent on the duration of stress. Stress can alter plasma corticosterone-binding globulin levels and AG administration can cause accumulation of the corticosterone biosynthetic precursor, adrenal cholesterol. In order to rule out these peripheral reasons for the hypersecretion of ACTH and corticosterone in our paradigm, we measured the plasma free fraction of corticosterone and adrenal mitochondrial cholesterol levels on day 2 after different pretreatments on day 1. AG+IMM60 pretreatment caused a significant increase in the plasma free fraction of corticosterone. Hypersecretion of ACTH and corticosterone in this group, despite an enhanced feedback signal, suggests central loci for the origin of facilitation. Also, AG treatment on day 1 did not result in accumulation of free or esterified adrenal cholesterol levels on day 2, and therefore cannot account for the hypersecretion of corticosterone. In our final study we attempted to determine if serotonin released during the first stressor is partially responsible for stress-induced facilitation of the HPA axis. We administered 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT), a 5HT1A agonist, either alone or in conjunction with stress and examined the effects of these pretreatments on the magnitude of facilitation. Interestingly, DPAT administered in lieu of stress produced facilitation similar in magnitude to that produced by IMM10. DPAT adminsitered in conjunction with IMM10 augmented stress-induced facilitation. Our results suggest that stress-induced facilitation of the HPA axis is associated with the release of serotonin during stress.

Keywords:
Corticotropin, Adrenal steroids, Stress, Serotonin
1.
Akana SF, Dallman MF, Bradbury MJ, Scribner KA, Strack AM, Walker CD: Feedback and facilitation in the adrenocortical system: Unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress. Endocrinology 1992;131:57–68.
2.
Dallman MF, Jones MT: Corticosterone feedback control of ACTH secretion: Effect of stress-induced corticosterone secretion on subsequent stress responses in the rat. Endocrinology 1973;92:1367–1375.
3.
Keller-Wood ME, Dallman MF: Corticosteroid inhibition of ACTH secretion. Endocr Rev 1984;5:1–24.
4.
Wong YN, Cassano WJ, D’mello AP: Acute stress-induced facilitation of the hypothalamic-pituitary-adrenal axis. Neuroendocrinology 2000;71:354–365.
5.
Mukai S, Okamoto M, Yamano T, Ishimura K, Fujita H: Cholesterol accumulation in adrenocortical mitochondria after ACTH-stimulation. Endocrinol Jpn 1984;31:177–184.
6.
Farese RV, Prudente WJ: On the role of intra-adrenal unesterified cholesterol in the steroidogenic effect of corticotropin. Biochim Biophys Acta 1978;544:77–84.
7.
Privalle CT, Crivello JF, Jefcoate CR: Regulation of intramitochondrial cholesterol transfer to side-chain cleavage cytochrome P-450 in rat adrenal gland. Proc Natl Acad Sci USA 1983;80:702–706.
8.
Feldman D, Mondon CE, Horner JA, Weiser JN: Glucocorticoid and estrogen regulation of corticosteroid-binding globulin production by rat liver. Am J Physiol 1979;237:E493–E499.
9.
Fleshner M, Deak T, Spencer RL, Laudenslager ML, Watkins LR, Maier SF: A long-term increase in basal levels of corticosterone and a decrease in corticosteroid-binding globulin after acute stressor exposure. Endocrinology 1995;136:45336–5342.
10.
Bhatnagar S, Dallman M: Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress. Neuroscience 1998;84:1025–1039.
11.
Vahabzadeh A, Fillenz M: Comparison of stress-induced changes in noradrenergic and serotonin neurons in the rat hippocampus using microdialysis. J Neurosci 1994;6:1205–1212.
12.
Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M, Aiso S, Kato R, Asai M: Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci 1995;15:1961–1970.
13.
Bagdy G, Calogero AE, Murphy DL, Szemeredi K: Serotonin agonists cause parallel activation of the sympathoadrenomedullary system and the hypothalamo-pituitary-adrenocortical axis in conscious rats. Endocrinology 1989;125:2664–2669.
14.
Calogero AE, Bernardini R, Margioris AN, Bagdy G, Gallucci WT, Munson PJ, Tamarkin L, Tomai TP, Brady L, Gold PW, Chrousos GP: Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami. Peptides 1989;10:189–200.
15.
Fuller RW, Snoddy HD: Serotonin receptor subtypes involved in the elevation of serum corticosterone concentration in rats by direct- and indirect-acting serotonin agonists. Neuroendocrinology 1990;52:206–211.
16.
Calogero AE, Bagdy G, Szemeredi K, Tartaglia ME, Gold PW, Chrousos GP: Mechanisms of serotonin receptor agonists-induced activation of the hypothalamic-pituitary-adrenal axis in the rat. Endocrinology 1990;126:1888–1894.
17.
Andrade R, Nicoll RA: Pharmacologically distinct actions of serotonin on single pyramidal neurons of the rat hippocampus recorded in vitro. J Physiol 1987;394:99–125.
18.
Wong YN, Chien BM, D’mello AP: Analysis of corticosterone in rat plasma by high-performance liquid chromatography, J Chromatogr Biomed Appl 1994;661:211–218.
19.
Bradbury MJ, Cascio CS, Scribner KA, Dallman MF: Stress-induced adrenocorticotropin secretion: Diurnal responses and decreases during stress in the evening are not dependent on corticosterone. Endocrinology 1991;128:680–688.
20.
Heider JG, Boyett RL: The picomole determination of free and total cholesterol in cells in culture. J Lipid Res 1978;19:514–518.
21.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265–275.
22.
Gann DS, Cryer GL, Pirkle JC Jr: Physiological inhibition and facilitation of adrenocortical responses to hemorrhage. Am J Physiol 1977;232:R5–R9.
23.
Shimizu N, Oomura Y, Aoyagi K: Electrochemical analysis of hypothalamic serotonin metabolism accompanied by immobilization stress in rats. Physiol Behav 1989;46:829–834.
24.
Culman J, Kvetnansky R, Torda T, Murgas K: Serotonin concentration in individual hypothalamic nuclei of rats exposed to acute immobilization stress. Neuroscience 1980;5:1503–1506.
25.
Culman J, Kiss A, Kvetnansky R: Serotonin and tryptophan hydroxylase in isolated hypothalamic and brainstem nuclei of rats exposed to acute and repeated immobilization stress. Exp Clin Endocrinol 1984;83:28–36.
26.
Mueller GP, Twohy CP, Chen HAT, Adis JP, Meites J: Effects of L-tryptophan and restraint stress on hypothalamic and brain serotonin turnover, and pituitary TSH, and prolactin release in rats. Life Sci 1976;18:715–724.
27.
Morgan WW, Rudeen PK, Pfeil KA: Effect of immobilization stress on serotonin content and turnover in regions of the rat brain. Life Sci 1975;17:143–150.
28.
Fuller RW: The involvement of serotonin in regulation of pituitary-adrenocortical function. Front Neuroendocrinol 1992;13:250–270.
29.
Van de Kar LD: Neuroendocrine pharmacology of serotonergic (5-HT) neurons. Annu Rev Pharmacol Toxicol 1991;31:298–320.
30.
Fuller RW: Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats. Behav Brain Res 1996;73:215–219.
31.
Chalmers DT, Watson SJ: Comparative anatomical distribution of 5-HT1a receptor mRNA and 5-HT1a binding in the rat brain: A combined in situ hybridisation/in vitro receptor autoradiographic study. Brain Res 1991;561:51–60.
32.
Oleskevich S, Descaries L: Quantified distribution of the serotonin innervation in adult rat hippocampus. Neuroscience 1990;34:19–33.
33.
Beck SG, Choi KC, List TJ, Okuhara DY, Birnstiel S: Corticosterone alters 5-HT1A receptor-mediated hyperpolarization in area CA1 hippocampal pyramidal neurons. Neuropsychopharmacology 1996;14:27–33.
34.
Beck SG, Choi KC, List TJ: Comparison of 5-hydroxytryptamine1A-mediated hyperpolarization in CA1 and CA3 hippocampal pyramidal cells. J Pharmacol Exp Ther 1992;263:350–359.
35.
Fuller RW, Snoddy HD: Influence of route of administration on potency of the selective 5HAT-1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, in rats. Res Commun Chem Pathol Pharmacol 1987;58:409–412.
36.
Vermes I, Telegdy G: The role of serotonergic transmission in the regulation of the hypothalamo-pituitary-adrenal function; in Lissak K (ed): Recent Developments of Neurobiology in Hungary. Budapest, Akademiai Kiado, 1976, vol 5, pp 5–25.
37.
Muller EE, Nistico G, Scapagnini U: Neurotransmitters and Anterior Pituitary Function. Academic Press, New York, 1977.
38.
Dunn AJ: Stress-related changes in cerebral catecholamine and indoleamine metabolism: Lack of effect of adrenalectomy and corticosterone. J Neurochem 1988;51:406–412.
© 2001 S. Karger AG, Basel
2001
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.