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

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 cDNA 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 LC-MS/MS. 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.

Neuroendocrinology of a Male-Specific Pattern for Depression Linked to Alcohol Use Disorder and Suicidal Behavior

“…Similarly, low levels of estradiol have been associated with more depressive symptoms in men (35). Carrier and colleagues report concomitant testosterone and estradiol administration to exhibit antidepressant-like effects in male gonadectomized rats, suggesting that testosterone’s protective effect may be mediated, in part, by its aromatization to estradiol (36). …”

Systems Pharmacology Based Study of the Molecular Mechanism of SiNiSan Formula for Application in Nervous and Mental Diseases

“…Interestingly, hepatic encephalopathy is caused by the function abnormal of the liver and the brain and has the same symptoms as the mental disorder [38]. Therefore, it is not difficult to speculate that there must be some connections between mental disorders and they exist in the lesions of multiple organs in neurological disorders [39] and endocrine abnormal [40]. …”

Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats

“…It remains to be determined whether the observed consequences of GNX on mPFC Zif268 expression is due to reductions in activity at androgen receptors or estrogen receptors. It is possible that testosterone or estrogen underlie many of the protective functions observed in intact animals, since previous reports have identified that both gonadal hormones promote mood-enhancing effects and target common molecular mechanisms for these effects (e.g., ERK1/2) (Carrier et al, 2015). Further support for the potential role of estrogen comes from evidence that androgen status (e.g., intact vs. GNX) did not impact novelty-induced expression of Zif268 within the male hippocampus (Kerr et al, 1996).…”