Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.
Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.
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DOI：
10.1016/j.brainres.2013.05.031
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发表时间：
2013-08-07
期刊：
影响因子：
2.9
通讯作者：
Jacobson L
中科院分区：
文献类型：
--
作者：
Vincent MY;Hussain RJ;Zampi ME;Sheeran K;Solomon MB;Herman JP;Khan A;Jacobson L
糖皮质激素受体（GR）参与抑郁症状和抗抑郁作用的位置仍不清楚。据报道，C57 B/6×129×CBA背景下前脑糖皮质激素受体缺失（FBGRKO-T50）会导致抑郁样行为增加和糖皮质激素升高。我们进一步假设前脑GR缺失会降低对糖皮质激素和抗抑郁药的行为敏感性。我们在纯C57 BL/6背景下的新创始者（FBGRKO-T29-1）的钙调蛋白激酶IIα-Cre介导的前脑GR缺失小鼠中验证了这一假设。我们测量不动性强迫游泳或尾部悬挂试验后操纵糖皮质激素或剂量反应实验后，与三环或单胺氧化酶抑制剂抗抑郁药。尽管前脑GR缺失至少与混合品系FBGRKO-T50小鼠中报道的一样迅速和更广泛，并且可能是因为它们的不同创始人，但我们的FBGRKO-T29-1小鼠没有表现出抑郁样行为或肾上腺皮质轴激素的增加。然而，FBGRKO-T29-1小鼠对糖皮质激素的抑郁作用和两种不同类型的抗抑郁药的作用至少与floxed GR对照一样敏感。FBGRKO-T29-1小鼠还意外地表现出盐皮质激素受体（MR）基因表达增加。我们的研究结果加强了以前的证据，抗抑郁作用不需要前脑GR，并建议抑郁样表型和合并MR上调和中央杏仁核GR缺乏症之间的相关性。我们的研究结果表明，在FBGRKO-T29-1小鼠靶向区域之外的GR参与糖皮质激素的抑郁作用，并留下了这些GR群体也有助于抗抑郁作用的可能性。
The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice, and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.
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影响因子：
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作者：
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DOI：
10.1073/pnas.0503878102
发表时间：
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影响因子：
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通讯作者：
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影响因子：
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