gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression.
gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression.
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DOI：
10.1016/j.biopsych.2010.04.024
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发表时间：
2010-09-15
影响因子：
10.6
通讯作者：
Luscher, Bernhard
中科院分区：
文献类型：
--
作者：
Shen, Qiuying;Lal, Rachnanjali;Luellen, Beth A.;Earnheart, John C.;Andrews, Anne Milasincic;Luscher, Bernhard
在小鼠胚胎中，γ2亚基基因的整体或前脑特异性杂合失活诱导的GABAA受体缺陷导致指示特质焦虑和抑郁状态的行为。相比之下，延迟到青春期的类似缺陷没有这些行为后果。在这里，我们描述了γ2缺陷小鼠的HPA轴异常和抗抑郁药物反应。我们分析了γ2+/−小鼠在新奇抑制喂养（NSFT）、强迫游泳（FST）、尾部悬吊（TST）和蔗糖消耗（SCT）试验中对地昔帕明和氟西汀的行为反应，以及GABAA受体缺陷和抗抑郁药物治疗诱导的血清皮质酮变化。成年γ2缺陷小鼠的基线皮质酮浓度升高与遗传损伤是否在胚胎发育期间诱导或延迟至青春期无关。然而，不同γ2缺陷小鼠品系的焦虑抑郁行为的表现与出生后发育期间的早发性HPA轴过度活跃相关。用氟西汀或地昔帕明对γ2+/−小鼠进行慢性而非亚慢性治疗使NSFT中的焦虑样行为正常化。此外，地昔帕明具有抗抑郁样作用，因为它使γ2+/−小鼠在FST、TST和SCT中的HPA轴功能和抑郁相关行为正常化。相比之下，氟西汀作为抗抑郁药无效，未能使HPA轴功能正常化。前脑中GABA能抑制的发育缺陷导致行为和内分泌异常以及指示焦虑抑郁障碍的选择性抗抑郁药物反应性，例如抑郁症，其通常以HPA轴活动过度和地昔帕明比氟西汀更有效为特征。
GABAA receptor deficits that are induced by global or forebrain-specific heterozygous inactivation of the γ2 subunit gene in mouse embryos result in behavior indicative of trait anxiety and depressive states. By contrast, a comparable deficit that is delayed to adolescence is without these behavioral consequences. Here we characterized γ2-deficient mice with respect to HPA axis abnormalities and antidepressant drug responses. We analyzed the behavioral responses of γ2+/− mice to desipramine and fluoxetine in Novelty Suppressed Feeding (NSFT), Forced Swim (FST), Tail Suspension (TST) and Sucrose Consumption (SCT) tests, as well as GABAA receptor deficit- and antidepressant drug treatment-induced alterations in serum corticosterone. Baseline corticosterone concentrations of adult γ2-deficient mice were elevated independent of whether the genetic lesion was induced during embryogenesis or delayed to adolescence. However, the manifestation of anxious-depressive behavior in different γ2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of γ2+/− mice with fluoxetine or desipramine normalized the anxiety-like behavior in the NSFT. Moreover, desipramine had antidepressant-like effects in that it normalized HPA axis function and depression-related behavior of γ2+/− mice in the FST, TST and SCT. By contrast, fluoxetine was ineffective as an antidepressant and failed to normalize HPA axis function. Developmental deficits in GABAergic inhibition in the forebrain cause behavioral and endocrine abnormalities and selective antidepressant drug responsiveness indicative of anxious-depressive disorders such as melancholic depression, which are frequently characterized by HPA axis hyperactivity and greater efficacy of desipramine vs. fluoxetine.
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影响因子：
5.3
作者：
Earnheart, John C.;Schweizer, Claude;Luscher, Bernhard
通讯作者：
Luscher, Bernhard
影响因子：
4.8
作者：
Hennings, Johannes M.;Owashi, Toshimi;Lucae, Susanne
通讯作者：
Lucae, Susanne
影响因子：
6.9
作者：
Austin, MP;Mitchell, P;Hadzi-Pavlovic, D
通讯作者：
Hadzi-Pavlovic, D
影响因子：
11
作者：
通讯作者：
--
影响因子：
3.6
作者：
Connor, TJ;Kelliher, P;Leonard, BE
通讯作者：
Leonard, BE