Biol Psychiat ：睾酮的抗抑郁机制被阐明

男性主要性激素——睾酮，表现出有抗抑郁药的性能，但其作用的确切机制仍不清楚。佛罗里达州立大学Nicole Carrier和Mohamed Kabbaj科学家们正在积极开展研究工作以弄清睾酮抗抑郁的机制。

研究人员已经发现，大脑海马区域参与记忆的形成和调节应激反应的特定信号途径在睾酮发挥抗抑郁过程中起着重要的作用，相关研究结果发表在《生物精神病学》杂志上。

与男性相比，女性患抑郁症的可能性高出了两倍多。男性性腺功能减退，体内雄性激素不产生或水平低，那么患有抑郁和焦虑的风险也会提高。睾酮替代疗法已被证明能有效地改善情绪。

尽管相关机制还不甚明了，了解睾酮是如何以及在何处发生功效的，科学家就能开发出更好地抗抑郁药物。

为了达到这一目标，科学家们在绝育的成年雄性大鼠上进行了多次实验。这些成年雄性大鼠患抑郁后，给予睾酮治疗后能逆转抑郁症相关行为。

Kabbaj说：“他们还发现了海马区一种叫MAPK/ERK2（丝裂原活化蛋白激酶/细胞外调节激酶2）的分子信号途径对睾酮抗抑郁中起着重要作用的。

这表明ERK2的正常运作是睾酮发挥抗抑郁作用的必要前提。这也表明这条信号通路可能是抗抑郁药治疗的新的潜在的靶标。

Kabbaj说：“有趣的是睾酮的抗抑郁功效并不与海马神经发生的变化（产生新的神经元）相关，这与其他经典抗抑郁药如丙咪嗪（Tofranil）和氟西汀（百忧解）不同。（生物谷：Bioon）

doi:10.1016/j.biopsych.2011.11.028
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Extracellular Signal-Regulated Kinase 2 Signaling in the Hippocampal Dentate Gyrus Mediates the Antidepressant Effects of Testosterone

Nicole Carrier, Mohamed Kabbaj

Background

Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression.

Methods

The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements.

Results

Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats.

Conclusions

These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.