Induction of Persistent Depressive-Like Behavior by Corticosterone

  • Shannon L. Gourley
  • Jane R. Taylor
Part of the Neuromethods book series (NM, volume 63)


Multiple biological processes are implicated in the neurobiology of depression based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that recapitulate the protracted feelings of anhedonia and helplessness that typify depression. In order to address this issue, the authors developed a protocol utilizing chronic oral exposure to the stress-associated adrenal hormone, corticosterone (CORT), in mice to induce anhedonic- and other depressive-like behaviors that are persistent for a significant duration of the animals’ lifespan, yet reversible by chronic antidepressant treatment. As we will discuss in this chapter, prior chronic CORT exposure has multiple behavioral consequences relevant to stress-related mood disorders despite normalization of blood serum CORT levels after weaning. An additional example (for which data are also provided) is persistently disrupted locomotor activity, suggestive of neurovegetative malaise and early waking, both characteristics of depression in humans. In sum, prior chronic CORT exposure provides an alternative method to chronic mild stress models of depression that is easily replicable and persistent, thereby modeling the chronic depressive-like state in humans.

Key words

Corticosterone Depression Anhedonia Antidepressant Stress Malaise 



The authors thank Dr. Florence Wu and Ms. Jacqueline Barker for their assistance with the locomotor analyses reported here. These experiments were supported by grants from the National Institutes of Health.


  1. 1.
    Kendler KS, Karkowski LM, Prescott CA (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156:837–841PubMedGoogle Scholar
  2. 2.
    de Kloet RE (2004) Hormones and the stressed brain. Ann N Y Acad Sci 1018:1–15PubMedCrossRefGoogle Scholar
  3. 3.
    Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of a sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 95:358–364Google Scholar
  4. 4.
    Willner P (2005) Chronic mild stress (CMS) revisited: Consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110PubMedCrossRefGoogle Scholar
  5. 5.
    Matthews K, Forbes N, Reid IC (1995) Sucrose consumption as an hedonic measure following chronic unpredictable mild stress. Physiol Behav 57:241–248PubMedCrossRefGoogle Scholar
  6. 6.
    Forbes NF, Stewart CA, Matthews K, Reid I (1996) Chronic mild stress and sucrose consumption: Validity as a model of depression. Physiol Behav 60:1481–1484PubMedCrossRefGoogle Scholar
  7. 7.
    Vollmayr B, Henn FA (2001) Learned helplessness in the rat: Improvements in validity and reliability. Brain Res Protoc 8:1–7CrossRefGoogle Scholar
  8. 8.
    Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25PubMedCrossRefGoogle Scholar
  9. 9.
    Catalani A, Casolini P, Scaccianoce S, Patacchioli FR, Spinozzi P, Angelucci L (2000) Maternal corticosterone during lactation permanently affects brain corticosteroid receptors, stress response and behaviour in rat progeny. Neuroscience 100:319–325PubMedCrossRefGoogle Scholar
  10. 10.
    Cinque C, Zuena AR, Casolini P, Ngomba RT, Melchiorri D, Maccari S, Nicoletti F, Gerevini D, Catalina A (2003) Reduced activity of hippocampal group 1 metabotropic glutamate receptors in learning-prone rats. Neuroscience 122:277–284PubMedCrossRefGoogle Scholar
  11. 11.
    Deroche V, Piazza PV, Deminiere J-M, Le Moal M, Simon H (1993) Rats orally self-administer corticosterone. Brain Research 622:315–320PubMedCrossRefGoogle Scholar
  12. 12.
    Piazza PV, Maccari S, Deminiere J-M, le Moal M, Mormede P, Simon H (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA 88:2088–2092PubMedCrossRefGoogle Scholar
  13. 13.
    Ardayfio P, Kim K-S (2006) Anxiogenic-like effects of chronic corticosterone in the light-dark emergence task in mice. Behav Neurosci 120:249–256PubMedCrossRefGoogle Scholar
  14. 14.
    Magariños AM, Orchinik M, McEwen BS (1998) Morphological changes in hippocampal CA3 regions induced by non-invasive glucocorticoid administration: a paradox. Brain Res 809:314–318PubMedCrossRefGoogle Scholar
  15. 15.
    Nacher J, Pham K, Gil-Fernandex V, McEwen BS (2004) Chronic restraint stress and chronic corticosterone treatment modulate differentially the expression of molecules related to structural plasticity in the adult rat piriform cortex. Neuroscience 126:503–509PubMedCrossRefGoogle Scholar
  16. 16.
    Pekary AE, Sattin A, Blood J, Furst S (2008) TRH and TRH-like peptide expression in rat following episodic or continuous corticosterone. Psychoneuroendocrinology 33:1183–1197PubMedCrossRefGoogle Scholar
  17. 17.
    Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR (2008a) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 63:353–359PubMedCrossRefGoogle Scholar
  18. 18.
    Gourley SL, Kiraly DD, Howell JL, Olausson P, Taylor JR (2008b) Acute hippocampal BDNF restores motivational and forced swim performance after corticosterone. Biol Psychiatry 64:884–890PubMedCrossRefGoogle Scholar
  19. 19.
    Gourley SL, Wu FJ, Taylor JR (2008c) Corticosterone regulates pERK1/2 in a chronic depression model. Ann N Y Acad Sci 1148:509–514PubMedCrossRefGoogle Scholar
  20. 20.
    Gourley SL, Kedves AT, Olausson P, Taylor JR (2009) A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsycho­pharmacology 34:707–716PubMedCrossRefGoogle Scholar
  21. 21.
    David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493PubMedCrossRefGoogle Scholar
  22. 22.
    Gourley SL, Taylor JR (2009) Recapitulation and reversal of a persistent depression-likesyndrome in rodent. Current Protocols in Neuroscience.  Chapter 9, Unit 9.32
  23. 23.
    Caldarone BJ, Karthigeyan K, Harrist A, Hunsberger JG, Witmack E, King SL, Jatlow P, Picciotto MR (2003) Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice. Psychopharmacology 170:94–101PubMedCrossRefGoogle Scholar
  24. 24.
    Gourley SL, Jacobs AM, Howell JL, Mo M, DiLeone RJ, Koleske AJ, Taylor JR (in revision) Action control is mediated by prefrontal BDNF and glucocorticoid receptor bindingGoogle Scholar
  25. 25.
    Shalev U, Kafkafi N (2002) Repeated maternal separation does not alter sucrose-reinforced and open-field behaviors. Pharmacol Biochem Behav 73:115–122PubMedCrossRefGoogle Scholar
  26. 26.
    Rüedi-Bettschen D, Pedersen E-M, Feldon J, Pryce CR (2005) Early deprivation under specific conditions leads to reduced interest in reward in adulthood in Wistar rats. Behav Brain Res 156:297–310PubMedCrossRefGoogle Scholar
  27. 27.
    Barr AM, Phillips AG (1999) Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology 141:99–106PubMedCrossRefGoogle Scholar
  28. 28.
    Russig H, Pezze M-A, Nanz-Bahr NI, Pryce CR, Feldon J, Murphy CA (2003) Amphetamine withdrawal does not produce a depressive-like state in rats as measured by three behavioral tests. Behav Pharmacol 14:1–18PubMedCrossRefGoogle Scholar
  29. 29.
    Barr AM, Phillips AG (1998) Chronic mild stress has no effect on responding by rats for sucrose under a progressive ratio schedule. Physiol Behav 64:591–597PubMedCrossRefGoogle Scholar
  30. 30.
    Goto M, Oshima I, Tomita T, Ebihara S (1989) Melatonin content of the pineal gland in different mouse strains. J Pineal Res 7:195–204PubMedCrossRefGoogle Scholar
  31. 31.
    Olivero A, Malorni W (1979) Wheel running and sleep in two strains of mice: Plasticity and rigidity in the expression of circadian rhythmicity. Brain Res 163:121–133CrossRefGoogle Scholar
  32. 32.
    Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606PubMedCrossRefGoogle Scholar
  33. 33.
    Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1767–1777Google Scholar
  34. 34.
    Schaaf MJM, Hoetelmans E, de Kloet R, Vreugdenhil E (1997) Corticosterone regulates expression of BDNF and trkB but not NT-3 and trkC mRNA in the rat hippocampus. J Neurosci Res 48:334–341PubMedCrossRefGoogle Scholar
  35. 35.
    Schaaf MJM, de Jong J, de Kloet ER, Vreugdenhil E (1998) Down-regulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain Res 813:112–120PubMedCrossRefGoogle Scholar
  36. 36.
    Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372PubMedGoogle Scholar
  37. 37.
    Prickaerts J, van den Hove DLA, Fieren FLP, Kia HK, Lenaerts I, Steckler T (2006) Chronic corticosterone manipulations in mice affect brain cell proliferation rates, but only partly affect BDNF protein levels. Neurosci Lett 396:12–16PubMedCrossRefGoogle Scholar
  38. 38.
    Laifenfeld D, Kerry R, Grauer E, Klein E, Ben-Shacher D (2005) Antidepressant and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity. Neurobiol Dis 20:432–441PubMedCrossRefGoogle Scholar
  39. 39.
    Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036PubMedGoogle Scholar
  40. 40.
    Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M (2004) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PediatricsEmory UniversityAtlantaUSA
  2. 2.Division of Molecular Psychiatry, Departments of Psychiatry and Psychology, Interdepartmental Neuroscience ProgramYale UniversityNew HavenUSA

Personalised recommendations