The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats.
The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats.
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DOI：
10.1016/j.biopsych.2014.12.024
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发表时间：
2015-08-15
影响因子：
10.6
通讯作者：
Kabbaj M
中科院分区：
文献类型：
--
作者：
Carrier N;Saland SK;Duclot F;He H;Mercer R;Kabbaj M
虽然睾丸激素水平对情感障碍的影响并不直接，但研究表明，这种激素可能会赋予男性一定程度的弹性。最近，我们证明了齿状回在介导睾酮对性腺切除雄性大鼠抑郁样行为的保护作用中的作用。在这里，睾酮可能通过雄激素受体介导的机制或通过局部芳构化雌二醇发挥其作用。性腺切除的雄性大鼠植入安慰剂，睾酮，或雌二醇丸，随后的保护性抗焦虑和抗抑郁样作用的睾酮及其芳香化代谢产物，雌二醇，然后分别在开放领域和蔗糖偏好测试进行了研究。此外，它们对海马基因表达的影响通过全基因组cDNA微阵列分析进行了分析。最后，睾酮的芳香化齿状回内的贡献进行了评估，通过局部输液的芳香化酶抑制剂，法倔唑，其疗效证实了LC-MS/MS。这两种激素具有抗抑郁样的作用与大量的重叠在转录调控，特别是在突触可塑性和丝裂原活化蛋白激酶途径相关的基因。此外，齿状回内的慢性芳香化酶抑制阻断了睾酮的保护作用。睾酮和雌二醇在性腺切除的雄性大鼠中表现出抗焦虑和抗抑郁样作用，同时同样调节这些行为的关键介质，表明共同的潜在机制。因此，我们证明，睾酮的保护作用是介导的，在一定程度上，其芳构化的齿状回。因此，这些研究结果提供了进一步了解雌二醇在介导睾酮的保护性抗焦虑和抗抑郁样作用中的作用。
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. 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. 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. 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.