Advertisement

Neuroscience Bulletin

, Volume 31, Issue 3, pp 288–296 | Cite as

Effects of testosterone and estradiol on anxiety and depressive-like behavior via a non-genomic pathway

  • Barbora Filova
  • Maria Malinova
  • Janka Babickova
  • Lubomira Tothova
  • Daniela Ostatnikova
  • Peter Celec
  • Julius HodosyEmail author
Original Article

Abstract

Besides their known slow genomic effects, testosterone and estradiol have rapid effects in the brain. However, their impact on mood-related behavior is not clear. The aim of this study was to investigate the non-genomic pathway of testosterone and estradiol in the amygdala in relation to anxiety and depressive-like behavior. Sham-operated and gonadectomized male rats (GDX) supplemented with testosterone propionate, estradiol, or olive oil were used. Five minutes after administration, anxiety and depression-like behavior were tested. Estradiol increased anxiolytic behavior in the open-field test compared to the GDX group, but administration of testosterone had no significant effect. Besides, c-Fos expression in the medial nucleus of the amygdala significantly increased after testosterone treatment compared to the GDX group, while no significant difference was observed in the central and the basolateral nuclei of the amygdala in the testosterone-treated group compared to the GDX group. In conclusion, estradiol had an anxiolytic effect via a rapid pathway, but no rapid effect of testosterone on anxiety was found. Further studies elucidating whether the rapid effect is mediated by a non-genomic pathway are needed.

Keywords

non-genomic effects steroids anxiety depression c-Fos amygdala 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Maggi A, Ciana P, Belcredito S, Vegeto E. Estrogens in the nervous system: mechanisms and nonreproductive functions. Annu Rev Physiol 2004, 66: 291–313.CrossRefPubMedGoogle Scholar
  2. [2]
    McEwen BS. Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 1991, 12: 141–147.CrossRefPubMedGoogle Scholar
  3. [3]
    Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol 2008, 29: 169–181.CrossRefPubMedCentralPubMedGoogle Scholar
  4. [4]
    Heinlein M. Plasmodesmata: dynamic regulation and role in macromolecular cell-to-cell signaling. Curr Opin Plant Biol 2002, 5: 543–552.CrossRefPubMedGoogle Scholar
  5. [5]
    Carrier N, Kabbaj M. Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone. Biol Psychiatry 2012, 71: 642–651.CrossRefPubMedCentralPubMedGoogle Scholar
  6. [6]
    Buddenberg TE, Komorowski M, Ruocco LA, Silva MA, Topic B. Attenuating effects of testosterone on depressive-like behavior in the forced swim test in healthy male rats. Brain Res Bull 2009, 79: 182–186.CrossRefPubMedGoogle Scholar
  7. [7]
    Hodosy J, Zelmanova D, Majzunova M, Filova B, Malinova M, Ostatnikova D, et al. The anxiolytic effect of testosterone in the rat is mediated via the androgen receptor. Pharmacol Biochem Behav 2012, 102: 191–195.CrossRefPubMedGoogle Scholar
  8. [8]
    Frye CA, Walf AA. Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites. Physiol Behav 2009, 97: 266–269.CrossRefPubMedCentralPubMedGoogle Scholar
  9. [9]
    Bitran D, Kellogg CK, Hilvers RJ. Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat. Horm Behav 1993, 27: 568–583.CrossRefPubMedGoogle Scholar
  10. [10]
    Aikey JL, Nyby JG, Anmuth DM, James PJ. Testosterone rapidly reduces anxiety in male house mice (Mus musculus). Horm Behav 2002, 42: 448–460.CrossRefPubMedGoogle Scholar
  11. [11]
    Edinger KL, Frye CA. Testosterone’s analgesic, anxiolytic, and cognitive-enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus. Behav Neurosci 2004, 118: 1352–1364.CrossRefPubMedGoogle Scholar
  12. [12]
    Fernandez-Guasti A, Martinez-Mota L. Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors. Psychoneuroendocrinology 2005, 30: 762–770.CrossRefPubMedGoogle Scholar
  13. [13]
    Frye CA, Rhodes ME, Dudek B. Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks. Brain Res 2005, 1036: 101–108.CrossRefPubMedCentralPubMedGoogle Scholar
  14. [14]
    Walf AA, Frye CA. A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology 2006, 31: 1097–1111.PubMedCentralPubMedGoogle Scholar
  15. [15]
    Galea LA, Lee TT, Kostaras X, Sidhu JA, Barr AM. High levels of estradiol impair spatial performance in the Morris water maze and increase ‘depressive-like’ behaviors in the female meadow vole. Physiol Behav 2002, 77: 217–225.CrossRefPubMedGoogle Scholar
  16. [16]
    Morgan MA, Pfaff DW. Effects of estrogen on activity and fear-related behaviors in mice. Horm Behav 2001, 40: 472–482.CrossRefPubMedGoogle Scholar
  17. [17]
    Walf AA, Frye CA. Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen. Steroids 2008, 73: 997–1007.CrossRefPubMedCentralPubMedGoogle Scholar
  18. [18]
    Filova B, Ostatnikova D, Celec P, Hodosy J. The effect of testosterone on the formation of brain structures. Cells Tissues Organs 2013, 197: 169–177.CrossRefPubMedGoogle Scholar
  19. [19]
    Kovacs KJ. Measurement of immediate-early gene activation-c-fos and beyond. J Neuroendocrinol 2008, 20: 665–672.CrossRefPubMedGoogle Scholar
  20. [20]
    Hoffman GE, Smith MS, Verbalis JG. c-Fos and related immediate early gene products as markers of activity in neuroendocrine systems. Front Neuroendocrinol 1993, 14: 173–213.CrossRefPubMedGoogle Scholar
  21. [21]
    Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 2011, 471: 358–362.CrossRefPubMedCentralPubMedGoogle Scholar
  22. [22]
    Rubinow DR, Schmidt PJ. Androgens, brain, and behavior. Am J Psychiatry 1996, 153: 974–984.CrossRefPubMedGoogle Scholar
  23. [23]
    Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, Hayashi S, et al. Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 2003, 144: 2055–2067.CrossRefPubMedGoogle Scholar
  24. [24]
    Sarkey S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D, DonCarlos LL. Classical androgen receptors in non-classical sites in the brain. Horm Behav 2008, 53: 753–764.CrossRefPubMedCentralPubMedGoogle Scholar
  25. [25]
    Walf AA, Frye CA. Estradiol reduces anxiety- and depression-like behavior of aged female mice. Physiol Behav 2010, 99: 169–174.CrossRefPubMedCentralPubMedGoogle Scholar
  26. [26]
    Michels G, Hoppe UC. Rapid actions of androgens. Front Neuroendocrinol 2008, 29: 182–198.CrossRefPubMedGoogle Scholar
  27. [27]
    Nabekura J, Oomura Y, Minami T, Mizuno Y, Fukuda A. Mechanism of the rapid effect of 17 beta-estradiol on medial amygdala neurons. Science 1986, 233: 226–228.CrossRefPubMedGoogle Scholar
  28. [28]
    Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 2003, 463: 3–33.CrossRefPubMedGoogle Scholar
  29. [29]
    Ennaceur A, Michalikova S, Chazot PL. Models of anxiety: responses of rats to novelty in an open space and an enclosed space. Behav Brain Res 2006, 171: 26–49.CrossRefPubMedGoogle Scholar
  30. [30]
    Crawley J, Goodwin FK. Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 1980, 13: 167–170.CrossRefPubMedGoogle Scholar
  31. [31]
    Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977, 229: 327–336.PubMedGoogle Scholar
  32. [32]
    Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates, 6th ed. New York: Academic Press, 2007: 456.Google Scholar
  33. [33]
    Gonzalez MI, Farabollini F, Albonetti E, Wilson CA. Interactions between 5-hydroxytryptamine (5-HT) and testosterone in the control of sexual and nonsexual behaviour in male and female rats. Pharmacol Biochem Behav 1994, 47: 591–601.CrossRefPubMedGoogle Scholar
  34. [34]
    Minkin DM, Meyer ME, van Haaren F. Behavioral effects of long-term administration of an anabolic steroid in intact and castrated male Wistar rats. Pharmacol Biochem Behav 1993, 44: 959–963.CrossRefPubMedGoogle Scholar
  35. [35]
    Balthazart J, Baillien M, Ball GF. Rapid control of brain aromatase activity by glutamatergic inputs. Endocrinology 2006, 147: 359–366.CrossRefPubMedGoogle Scholar
  36. [36]
    Diaz-Veliz G, Alarcon T, Espinoza C, Dussaubat N, Mora S. Ketanserin and anxiety levels: influence of gender, estrous cycle, ovariectomy and ovarian hormones in female rats. Pharmacol Biochem Behav 1997, 58: 637–642.CrossRefPubMedGoogle Scholar
  37. [37]
    Trainor BC, Finy MS, Nelson RJ. Rapid effects of estradiol on male aggression depend on photoperiod in reproductively non-responsive mice. Horm Behav 2008, 53: 192–199.CrossRefPubMedCentralPubMedGoogle Scholar
  38. [38]
    Vasudevan N, Pfaff DW. Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles. Endocr Rev 2007, 28: 1–19.CrossRefPubMedGoogle Scholar
  39. [39]
    Duncan GE, Knapp DJ, Breese GR. Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety. Brain Res 1996, 713: 79–91.CrossRefPubMedGoogle Scholar
  40. [40]
    Heinlein CA, Chang C. The roles o f androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 2002, 16: 2181–2187.CrossRefPubMedGoogle Scholar
  41. [41]
    Nagypal A, Wood RI. Region-specific mechanisms for testosterone-induced Fos in hamster brain. Brain Res 2007, 1141: 197–204.CrossRefPubMedCentralPubMedGoogle Scholar
  42. [42]
    Kovacs KJ, Sawchenko PE. Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons. J Neurosci 1996, 16: 262–273.PubMedGoogle Scholar
  43. [43]
    Vasudevan N, Pfaff DW. Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol 2008, 29: 238–257.CrossRefPubMedGoogle Scholar
  44. [44]
    Nyby JG. Reflexive testosterone release: a model system for studying the nongenomic effects of testosterone upon male behavior. Front Neuroendocrinol 2008, 29: 199–210.CrossRefPubMedCentralPubMedGoogle Scholar
  45. [45]
    Cornil CA, Taziaux M, Baillien M, Ball GF, Balthazart J. Rapid effects of aromatase inhibition on male reproductive behaviors in Japanese quail. Horm Behav 2006, 49: 45–67.CrossRefPubMedCentralPubMedGoogle Scholar
  46. [46]
    Cross E, Roselli CE. 17beta-estradiol rapidly facilitates chemoinvestigation and mounting in castrated male rats. Am J Physiol 1999, 276: R1346–1350.PubMedGoogle Scholar
  47. [47]
    Malmnas CO. Short-latency effect of testosterone on copulatory behaviour and ejaculation in sexually experienced intact male rats. J Reprod Fertil 1977, 51: 351–354.CrossRefPubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Barbora Filova
    • 1
  • Maria Malinova
    • 1
  • Janka Babickova
    • 1
    • 5
  • Lubomira Tothova
    • 1
    • 5
  • Daniela Ostatnikova
    • 2
  • Peter Celec
    • 1
    • 3
    • 4
    • 5
  • Julius Hodosy
    • 1
    • 2
    • 5
    Email author
  1. 1.Institute of Molecular Biomedicine, Faculty of MedicineComenius UniversityBratislavaSlovakia
  2. 2.Institute of Physiology, Faculty of MedicineComenius UniversityBratislavaSlovakia
  3. 3.Institute of Pathophysiology, Faculty of MedicineComenius UniversityBratislavaSlovakia
  4. 4.Department of Molecular Biology, Faculty of Natural SciencesComenius UniversityBratislavaSlovakia
  5. 5.Center for Molecular MedicineSlovak Academy of SciencesBratislavaSlovakia

Personalised recommendations