DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System
DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System
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DOI：
10.1038/npp.2008.46
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发表时间：
2009-02-01
影响因子：
7.6
通讯作者：
Yadid, Gal
中科院分区：
文献类型：
--
作者：
Genud, Rotem;Merenlender, Avia;Yadid, Gal
大脑中脱氢表雄酮（DHEA）水平的改变可以变构调节γ-氨基丁酸-A型（GABA（A）R）、N-甲基-D-天冬氨酸（NMDAR）和Sigma-1（Sigma 1 R）受体。在人类中，DHEA具有抗抑郁作用;然而，其机制尚不清楚。我们研究了DHEA的改变是否也发生在抑郁症的动物模型中，弗林德斯敏感线（FSL）大鼠，目的是确定DHEA作用的大脑部位及其抗抑郁机制。我们发现，与SD对照组相比，FSL大鼠与抑郁有关的某些脑区的DHEA水平较低。此外，DHEA（1 mg/kg IP，持续14天）给药的FSL大鼠在强迫游泳试验中比FSL对照组具有更多的移动的。在NAc和VTA中，与SD大鼠相比，在FSL大鼠中观察到GABA（A）δ亚基水平的显著变化，但sigma 1 R mRNA水平无显著变化。δ-亚单位控制GABA（A）R对神经类固醇的敏感性。事实上，用GABA（A）激动剂蝇蕈醇（0.5 mg/kg）与DHEA（GABA（A）的负调节剂）一起治疗（14天）FSL大鼠，逆转了DHEA对游泳试验中不动性的影响。向FSL大鼠的VTA和NAc中灌注DHEA硫酸盐（DHEAS）（3 nM和30 nM，持续14天）改善了它们在游泳测试中的表现，持续治疗后至少3周。我们的研究结果表明DHEA的改变参与了抑郁症的病理生理学，并且DHEA的抗抑郁作用是通过NAc和VTA中的GABA（A）Rs介导的。
Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate gamma-aminobutyric-acid-type-A (GABA(A)R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (sigma 1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the delta-subunit of GABA(A), but not of sigma 1R mRNA, in FSL rats compared to SD rats. The delta-subunit controls the sensitivity of the GABA(A)R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA(A) agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA(A)), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA(A)Rs in the NAc and VTA.