Stressful stimuli are known to affect glucocorticoid receptor (GR) mRNA levels in the rat brain. The aim of this study was to examine the duration of chronic stress-induced changes in GR gene expression in the male rat hippocampus and cerebellum. By using in situ hybridization histochemistry, we detected a statistically significant down-regulation of GR mRNA both in the hippocampus and in the cerebellum of rats stressed for 8, 10 and 14 days. The same degree of down-regulation could also be detected in the above brain areas of rats stressed for 14 days and left undisturbed for 48 h or 8 days after stress. To examine the effects of subsequent stressors on the expression of down-regulated GR mRNA in the hippocampus of chronically stressed rats, we determined, by Northern blotting, GR mRNA levels in the hippocampi of rats stressed for 14 days and subsequently exposed to either short- or long-duration stressors. The down-regulated levels of GR mRNA remained practically unaffected when a subsequent new stressor was applied. Our results show that chronic stress-induced down-regulation of GR mRNA in the rat brain can be extended for periods longer than the initial/causative stimulus, irrespective of the presence of a novel stimulus.

1.
Jacobson L, Sapolsky RM: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenal axis. Endocr Rev 1991;12:118–134.
2.
Diorio D, Viau V, Meaney MJ: The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13:3839–3847.
3.
Dallman MF, Akana SF, Levin N, Walker C-D, Bradbury MJ, Suemaru S, Scribner KS: Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. Ann NY Acad Sci 1994;746:22–31.
4.
de Kloet ER: Brain corticosteroid receptor balance and homeostatic control. Front Neuroendocrinol 1991;12:95–164.
5.
Weinstock M, Matlina E, Maor GI, Rosen H, McEwen BS: Prenatal stress selectively alters reactivity of the hypothalamic-pituitary-adrenal system in the female rat. Brain Res 1992;595:195–198.
6.
McCormick CM, Smythe J, Sharma S, Meaney MJ: Sex-dependent effects of prenatal stress on the development of brain corticosteroid receptor systems and hypothalamic-pituitary-adrenal responses to stress. Dev Brain Res 1994;79:260–266.
7.
Fameli M, Kitraki E, Stylianopoulou F: Effects of hyperactivity of the maternal hypothalamic-pituitary-adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamines of the offspring. Int J Dev Neurosci 1994;12:651–659.
8.
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM: Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev Neurosci 1996;18:49–72.
9.
Sapolsky RM, Krey LC, McEwen BS: Stress down-regulates glucocorticoid receptors in a site-specific manner in the brain. Endocrinology 1984;114:287–292.
10.
Sapolsky RM, Meaney MJ, McEwen BS: The development of glucocorticoid receptor system in the rat limbic brain. III. Negative-feedback regulation. Dev Brain Res 1985;18:169–173.
11.
Herman JP, Adams D, Prewitt C: Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 1995;61:180–190.
12.
Makino S, Smith MA, Gold PW: Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: Association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 1995;136:3299–3309.
13.
Rosewicz S, McDonald AR, Maddux BA, Goldfine ID, Miesfeld RL, Logsdon CD: Mechanism of glucocorticoid receptor down-regulation by glucocorticoids. J Biol Chem 1988;263:2581–2584.
14.
Hoeck W, Rusconi S, Groner B: Down-regulation and phosphorylation of glucocorticoid receptors in cultured cells. J Biol Chem 1989;264:14396–14402.
15.
Dong Y, Poellinger L, Gustafsson J-A, Okret S: Regulation of glucocorticoid receptor expression: Evidence for transcriptional and posttranslational mechanisms. Mol Endocrinol 1988;2:1256–1264.
16.
Webster JC, Cidlowski JA: Downregulation of the glucocorticoid receptor. A mechanism for physiological adaptation to hormones. Ann NY Acad Sci 1994;746:216–220.
17.
van Dijken HH, de Goeij DCE, Sutanto W, Mos J, de Kloet RE, Tilders FJH: Short inescapable stress produces long-lasting changes in the brain-pituitary-adrenal axis of adult male rats. Neuroendocrinology 1993;58:57–64.
18.
Kitraki E, Alexis MN, Papalopoulou M, Stylianopoulou F: Glucocorticoid receptor gene expression in the embryonic rat brain. Neuroendocrinology 1996;63:305–317.
19.
Miesfeld R, Rusconi S, Godowski PJ, Maler BA, Okret S, Wikstrom AC, Gustafsson J-A, Yamamoto KR: Genetic complementation of a glucocorticoid receptor deficiency by expression of cloned receptor cDNA. Cell 1986;46:389–399.
20.
Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. San Diego, Academic Press, 1986.
21.
Kitraki E, Bozas E, Philippidis H, Stylianopoulou F: Aging-related changes in IGF-II and c-fos gene expression in the rat brain. Int J Dev Neurosci 1993;11:1–9.
22.
Chromczynski P, Sacchi N: Single-step method of RNA isolation by guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
23.
Fort P, Marty L, Piechaczyk M, El Sabrouty SE, Dani C, Jeanteur P, Blanchard JM: Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res 1985;13:1431–1442.
24.
Watanabe Y, Gould E, McEwen BS: Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 1992;588:341–345.
25.
Gray JA: Fear and the central nervous system; in Gray JA (ed): The Psychology of Fear and Stress. London, Cambridge University Press, 1991, pp 272–331.
26.
Chao HM, Choo PH, McEwen BS: Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain. Neuroendocrinology 1989;50:365–371.
27.
Bohn MC, O’Banion MK, Young DA, Guiliano R, Hussain S, Dean DO, Cunningham LA: In vitro studies of glucocorticoid effects on neurons and astrocytes. Ann NY Acad Sci 1994;746:243–259.
28.
Herman JP, Spencer R: Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo. J Neurosci 1998;18:7462–7473.
29.
Young EA, Akana S, Dallman MF: Decreased sensitivity to glucocorticoid fast feedback in chronically stressed rats. Neuroendocrinology 1990;51:536–542.
30.
Marti O, Gavalda A, Gomez F, Armario A: Direct evidence for chronic stress-induced facilitation of the adrenocorticotropin response to a novel acute stressor. Neuroendocrinology 1994;60:1–7.
31.
Zong J, Ashraf J, Thompson EB: The promoter and first, untranslated exon of the human glucocorticoid receptor gene are GC rich but lack consensus glucocorticoid receptor element sites. Mol Cell Biol 1990;10:5580–5585.
32.
Drouin J, Sun YL, Chamberland M, Gauthier Y, De Lean A, Nemer M, Schmidt TJ: Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J 1993;12:145–156.
33.
Ghosh A, Greenberg ME: Calcium signaling in neurons: Molecular mechanisms and cellular consequences. Science 1995;268:239–247.
34.
Trapp T, Rupprecht R, Castren M, Reul JMHM, Holsboer F: Heterodimerization between mineralocorticoid and glucocorticoid receptor: A new principle of glucocorticoid action in the CNS. Neuron 1994;13:1457–1462.
35.
Van Steensel B, Van Binnendijk E, Hornsby CD, Van der Voort HTM, De Kloet ER, Van Driel R: Partial colocalization of glucocorticoid and mineralocorticoid receptors in discrete compartments in nuclei of rat hippocampus neurons. J Cell Sci 1996;109:787–792.
36.
Fryer CJ, Nordeen SK, Archer TK: Antiprogestins mediate differential effects on glucocorticoid receptor remodeling of chromatin structure. J Biol Chem 1998;273:1175–1183.
37.
Vig E, Barrett TJ, Vedeckis WV: Coordinate regulation of glucocorticoid receptor and c-jun mRNA levels: Evidence for cross-talk between two signaling pathways at the transcriptional level. Mol Endocrinol 1994;8:1336–1346.
38.
Sloviter R, Valiquette G, Abrams GM, Ronk EC, Solls AI, Paul LA, Neubort SL: Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 1989;243:535–538.
39.
McEwen BS, Gould EA, Sakai RR: The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress. Br J Psychiatry Suppl 1992;15:18–23.
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