Abstract
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
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Article info
Publication history
Published online: January 14, 2015
Accepted:
December 19,
2014
Received in revised form:
December 3,
2014
Received:
September 30,
2014
Footnotes
Authors NC and SKS contributed equally to this work.
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
