The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats

Biol Psychiatry. 2015 Aug 15;78(4):259-69. doi: 10.1016/j.biopsych.2014.12.024. Epub 2015 Jan 14.


Background: While the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone's protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol.

Methods: Gonadectomized male rats were implanted with a placebo, testosterone, or estradiol pellet, and subsequent protective anxiolytic- and antidepressant-like effects of testosterone and its aromatized metabolite, estradiol, were then investigated in the open field and sucrose preference tests, respectively. Moreover, their influence on gene expression in the hippocampus was analyzed by genome-wide complementary DNA microarray analysis. Finally, the contribution of testosterone's aromatization within the dentate gyrus was assessed by local infusion of the aromatase inhibitor fadrozole, whose efficacy was confirmed by liquid chromatography-tandem mass spectrometry.

Results: Both hormones had antidepressant-like effects associated with a substantial overlap in transcriptional regulation, particularly in synaptic plasticity- and mitogen-activated protein kinase pathway-related genes. Further, chronic aromatase inhibition within the dentate gyrus blocked the protective effects of testosterone.

Conclusions: Both testosterone and estradiol exhibit anxiolytic- and antidepressant-like effects in gonadectomized male rats, while similarly regulating critical mediators of these behaviors, suggesting common underlying mechanisms. Accordingly, we demonstrated that testosterone's protective effects are mediated, in part, by its aromatization in the dentate gyrus. These findings thus provide further insight into a role for estradiol in mediating the protective anxiolytic- and antidepressant-like effects of testosterone.

Keywords: Anxiety; Aromatase; Depression; Estradiol; Hippocampus; Testosterone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Anxiety Agents / administration & dosage
  • Antidepressive Agents / administration & dosage
  • Anxiety / genetics
  • Anxiety / metabolism*
  • Anxiety / physiopathology*
  • Aromatase Inhibitors / pharmacology
  • Castration
  • Depression / genetics
  • Depression / metabolism*
  • Depression / physiopathology*
  • Estrogens / administration & dosage
  • Estrogens / physiology*
  • Fadrozole / pharmacology
  • Gene Expression / drug effects
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • Male
  • Motor Activity / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Testosterone / administration & dosage
  • Testosterone / metabolism
  • Testosterone / physiology*


  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Aromatase Inhibitors
  • Estrogens
  • Testosterone
  • Fadrozole