Neurochemical Research

, Volume 33, Issue 4, pp 637–642 | Cite as

From the Stalk to Down Under about Brain Glucocorticoid Receptors, Stress and Development

Original Paper


George Fink witnessed the birth of modern neuroendocrinology while examining with Geoffrey Harris the secrets of the pituitary stalk secretagogs. From thereon neuroendocrine systems were identified that linked experience and behavior with hormone secretion and action. A prime example of this integration of body and mind with the environment is provided by the corticosteroid hormones released from the adrenals in one hour pulses and after stress. Corticosteroids coordinate cell and organ function with membrane properties and gene transcription over time spans from milliseconds to hours, days, weeks and even a life time. Here we report that also the receptors display a remarkable plasticity in determining the fate of an organism.


Brain Pituitary Stress hormones Development Denervation Mineralocorticoid receptors Glucocorticoid receptors 


  1. 1.
    Wade N (1981) The Nobel duel; two scientists’ 21–year race to win the world’s most coveted research prize. Anchor Press/Doubleday, New York, pp 1–321Google Scholar
  2. 2.
    Raisman G (1997) Geoffrey Harris and the discovery of the neural control of the pituitary. Ann Rev Neurosci 20:533–566PubMedCrossRefGoogle Scholar
  3. 3.
    Fink G (1967) Nature of luteinizing hormone releasing factor in hypophysial portal blood. Nature 215:159–161PubMedCrossRefGoogle Scholar
  4. 4.
    Fink G, Smith JR, Tibballs J (1971) Corticotrophin releasing factor in hypophysial portal blood of rats. Nature 230:467–468PubMedCrossRefGoogle Scholar
  5. 5.
    Fink G, Harris GW (1970) The luteinizing hormone releasing activity of extracts of blood from the hypophysial portal vessels of rats. J Physiol 208:221–241PubMedGoogle Scholar
  6. 6.
    Clarke IJ (2002) Two decades of measuring GnRH secretion. Reprod Suppl 59:1–13PubMedGoogle Scholar
  7. 7.
    De Kloet ER (2006) From punch to profile. Neurochem Res 31:131–135PubMedCrossRefGoogle Scholar
  8. 8.
    Dorsa DM, de Kloet ER, Mezey É et al (1979) Pituitary-brain transport of neurotensin: functional significance of retrograde transport. Endocrinology 104:1663–1666PubMedGoogle Scholar
  9. 9.
    De Kloet ER, Drago F, Mezey É et al (1983) Pituitary stalk section transiently impairs the acquisition of shuttle box avoidance behavior. Physiol Behav 30:499–502PubMedCrossRefGoogle Scholar
  10. 10.
    Mezey É, Palkovits M, de Kloet ER et al (1978) Evidence for pituitary-brain transport of a behaviorally potent ACTH analog. Life Sci 22:831– 838PubMedCrossRefGoogle Scholar
  11. 11.
    De Wied D (1997) The neuropeptide story. Front Neuroendocrinol 18:101–113PubMedCrossRefGoogle Scholar
  12. 12.
    Young LJ (1999) Frank A. Beach Award. Oxytocin and vasopressin receptors and species-typical social behaviors. Horm Behav 36:212–221PubMedCrossRefGoogle Scholar
  13. 13.
    De Kloet ER, Rotteveel F, Voorhuis TAM et al (1985) Topography of binding sites for neurohypohyseal hormones in rat brain. Eur J Pharmacol 110:113–119PubMedCrossRefGoogle Scholar
  14. 14.
    Voorhuis TAM, De Kloet ER, De Wied D (1991) Effect of a vasotocin analog on singing behavior in the canary. Horm Behav 25:549–559PubMedCrossRefGoogle Scholar
  15. 15.
    Landgraf R (2006) The involvement of the vasopressin system in stress-related disorders. CNS Neurol Disord Drug Targets 5:167–179PubMedGoogle Scholar
  16. 16.
    De Kloet ER, Joëls M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475PubMedCrossRefGoogle Scholar
  17. 17.
    De Kloet ER, Van der Vies J, De Wied D (1974) The site of the suppressive action of dexamethasone on pituitary-adrenal activity. Endocrinology 94:61–73PubMedGoogle Scholar
  18. 18.
    De Kloet ER, Wallach G, McEwen BS (1975) Difference in binding of corticosterone and dexamethasone to rat brain and pituitary. Endocrinology 96:598–611PubMedCrossRefGoogle Scholar
  19. 19.
    Ising M, Kunzel HE, Binder EB, Nickel T, Modell S, Holsboer F (2005) The combined dexamethasone/CRH test as a potential surrogate marker in depression. Progr Neuropsychopharmacol Biol Psych 29:1085–1093CrossRefGoogle Scholar
  20. 20.
    Meijer OC, de Lange ECM, Breimer DD et al (1998) Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139:1789–1793PubMedCrossRefGoogle Scholar
  21. 21.
    Karssen AM, Meijer OC, Berry A et al (2005) Low doses of dexamethasone can produce a hypocorticosteroid state in the brain. Endocrinology 146:5587–5595PubMedCrossRefGoogle Scholar
  22. 22.
    Reul JMHM, De Kloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117:2505–2511PubMedGoogle Scholar
  23. 23.
    Karst H, Berger S, Turiault M (2005) Mineralocorticoid receptors are indispensable for non-genomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci USA 102:19204–19207PubMedCrossRefGoogle Scholar
  24. 24.
    Olijslagers JE, de Kloet ER, Joëls M, Karst H (2006) Rapid enhancement of hippocampal glutamate transmission by corticosterone is mediated via the MEK/ERK pathway. FENS Forum Meeting, abstract 152.17Google Scholar
  25. 25.
    Joëls M, Pu Z, Wiegert O et al (2006) Learning under stress: how does it work? Trends Cogn Sci 10:152–158PubMedCrossRefGoogle Scholar
  26. 26.
    Young EA, Abelson J, Lightman SL (2004) Cortisol pulsatility and its role in stress regulation and health. Front Neuroendocrinol 25:69–76PubMedCrossRefGoogle Scholar
  27. 27.
    Bohus B, De Kloet ER (1981) Adrenal steroids and extinction behaviour: antagonism by progesterone, deoxycorticosterone and dexamethasone of a specific affect of cortico-sterone. Life Sci 28:433–440PubMedCrossRefGoogle Scholar
  28. 28.
    Kruk MR, Halász J, Meelis W et al (2004) Fast positive feedback between the adrenocortical stress response and a brain mechanism involved in aggressive behavior. Behav Neurosci 118:1062–1070PubMedCrossRefGoogle Scholar
  29. 29.
    Oitzl MS, Reichardt HM, Joëls M, De Kloet ER (2001) Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory. PNAS 98:2790–2795CrossRefGoogle Scholar
  30. 30.
    Meijer OC, Kalkhoven E, van der Laan S et al (2005) Steroid receptor co-activator-1 splice variants differentially affect corticosteroid receptor signalling. Endocrinology 146:1438–1448PubMedCrossRefGoogle Scholar
  31. 31.
    Rahmouni K, Sibug RM, de Kloet ER et al (2002) Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension. Eur J Pharmacol 436:207–216PubMedCrossRefGoogle Scholar
  32. 32.
    DeRijk RH, Wust S, Meijer OC et al (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 91:5083–5089PubMedCrossRefGoogle Scholar
  33. 33.
    De Kloet ER, Vreugdenhil E, Oitzl MS et al (1998) Brain corticosteroid receptor balance in health and disease. Endocr Rev.19:269–301Google Scholar
  34. 34.
    De Kloet ER, de Rijk RH, Meijer OC (2007). Therapy insight: Is there an imbalance response of mineralocorticoid and glucocorticoid receptors in depression? Nat. Clin Pract Endocrinol Metab 3:168–179CrossRefGoogle Scholar
  35. 35.
    Nyakas C, De Kloet ER, Veldhuis D et al (1983) Hippocampal corticosterone receptors and novelty-induced behavioral activity: effect of kainic acid lesion in the hippocampus. Brain Res 288:219–228PubMedCrossRefGoogle Scholar
  36. 36.
    De Ronde FSW, De Kloet ER, Nyakas C (1986) Corticosteroid receptor plasticity and recovery of a deficient hippocampus-associated behavior after unilateral (dorsal) hippocampectomy. Brain Res 374:219–226PubMedCrossRefGoogle Scholar
  37. 37.
    Maccari S, Mormède P, Piazza PV et al (1992) Hippocampal type I and type II corticosteroid receptors are modulated by central noradrenergic systems. Psychoneuroendocrinol 17:103–112CrossRefGoogle Scholar
  38. 38.
    Seckl JR, Fink G (1991) Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines. J Steroid Biochem Mol Biol 40:685–688PubMedCrossRefGoogle Scholar
  39. 39.
    De Kloet ER, van Eekelen JAM, Seger MA (1988) Glucocorticoid and lesion-induced plasticity. In: Flohr H (ed) Post-lesion neural plasticity. Springer-Verlag, Berlin, pp 637–644Google Scholar
  40. 40.
    Antakly T, Sasaki A, Liotta AS et al (1985) Induced expression of the glucocorticoid receptor in the rat intermediate pituitary lobe. Science 229:277–279PubMedCrossRefGoogle Scholar
  41. 41.
    Seger MA, van Eekelen JAM, Kiss JZ et al (1988) Stimulation of pro-opiomelanocortin gene expression by glucocorticoids in the denervated rat intermediate pituitary gland. Neuroendocrinol 47:350–357Google Scholar
  42. 42.
    Han F, Ozawa H Matsuda KI et al (2007) Changes in the expression of corticotrophin-releasing hormone, mineralocorticoid receptor and glucocorticoid receptor mRNAs in the hypothalamic paraventricular nucleus induced by fornix transection and adrenalectomy. J Neuroendocrinol 19:229–238PubMedCrossRefGoogle Scholar
  43. 43.
    Rosenfeld P, Sutanto W, Levine S et al (1988) Ontogeny of Type I and Type II corticosteroid receptors in the rat hippocampus. Dev Brain Res 42:113–118CrossRefGoogle Scholar
  44. 44.
    Van Eekelen JAM, Rosenfeld P, Levine S et al (1987) Post-natal disappearance of glucocorticoid receptor immunoreactivity. Neurosci Res Comm 1:129–133Google Scholar
  45. 45.
    Rosenfeld P, van Eekelen JAM, Levine S et al (1988) Ontogeny of the Type 2 glucocorticoid receptor in discrete rat brain regions: an immunocytochemical study. Dev Brain Res 42:119–127CrossRefGoogle Scholar
  46. 46.
    Van Eekelen JAM, Bohn MC, De Kloet ER (1991) Postnatal ontogeny of mineralocorticoid and glucocorticoid receptor gene expression in regions of the rat tel- and diencephalon. Dev Brain Res 61:33–43CrossRefGoogle Scholar
  47. 47.
    Fink G (1995) The self-priming effect of LHRH: a unique servomechanism and possible cellular model for memory. Front Neuroendocrinol 16:183–190PubMedCrossRefGoogle Scholar
  48. 48.
    Fink G, Sarkar DK, Dow RC et al (1982) Sex difference in response to alphaxalone anaesthesia may be oestrogen dependent. Nature 15:270–272CrossRefGoogle Scholar
  49. 49.
    Fink G, Sumner BE (1996) Oestrogen and mental state. Nature 26:306CrossRefGoogle Scholar
  50. 50.
    Han, Ozawa H, Matsuda K et al (2005) Colocalization of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus and hypothalamus. Neurosci Res 51:371–381PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • E. Ronald de Kloet
    • 1
  • Fang Han
    • 1
  • Onno C. Meijer
    • 1
  1. 1.Division of Medical PharmacologyLACDR/LUMCLeidenThe Netherlands

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