Chronic exposure to anabolic androgenic steroids alters neuronal function in the mammalian forebrain via androgen receptor- and estrogen receptor-mediated mechanisms.
Chronic exposure to anabolic androgenic steroids alters neuronal function in the mammalian forebrain via androgen receptor- and estrogen receptor-mediated mechanisms.
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DOI：
10.1523/jneurosci.3108-09.2009
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发表时间：
2009-10-07
期刊：
影响因子：
--
通讯作者：
Henderson LP
中科院分区：
文献类型：
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作者：
Penatti CA;Porter DM;Henderson LP
合成雄激素可促进对社会行为的不良影响，其中γ-氨基丁酸A型受体(GABA A)受体介导的前脑环路在其中起着关键作用。虽然所有的AAs都与雄激素受体(AR)结合，但它们也可能被芳香化为雌激素，从而潜在地通过雌激素受体(ER)传递效应。野生型雄性小鼠长期暴露于化学成分不同的AAS增加的动作电位(AP)频率、选择性GABAA受体亚单位mRNAs和内侧视前区(MPOA)的GABA能突触电流衰减的组合中。用药物和在AR缺乏的TFM突变小鼠身上进行的实验表明，AAS依赖的增强野生型小鼠的GABA能传递是由AR介导的。在AR缺乏的小鼠中，AAS引起显著不同的效应，降低AP频率、sIPSC幅度和频率以及选择性GABAA受体亚单位mRNAs的表达。令人惊讶的是，在没有AR信号的情况下，数据表明AAS并不是ER激动剂，而是一种新的体内作用，AAS抑制芳香酶并损害内源性ER信号。这些结果表明，AAS具有通过多种类固醇信号机制改变前脑神经元功能的能力，提示这些类固醇在大脑中的作用不仅取决于AR-和ER介导的对不同靶基因的调节的平衡，还取决于这些药物改变类固醇代谢从而改变内源性类固醇环境的能力。
Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu.