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糖皮质激素受体拮抗作用增强了氟西汀诱导的5-羟色胺转运体下调。

Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter.

作者信息

Johnson Daniel Anthony, Ingram Colin David, Grant Emma Jane, Craighead Mark, Gartside Sarah Elizabeth

机构信息

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Neuropsychopharmacology. 2009 Jan;34(2):399-409. doi: 10.1038/npp.2008.70. Epub 2008 May 21.

Abstract

The effects of combined treatment with a glucocorticoid receptor (GR) antagonist, Org 34850, and a selective serotonin reuptake inhibitor (SSRI), fluoxetine, were investigated on pre- and postsynaptic aspects of 5-HT neurotransmission. Rats were treated for 14 days with Org 34850 (15 mg per kg per day subcutaneously), fluoxetine (10 mg per kg per day intraperitoneally), or a combination of both drugs. [(3)H]-citalopram binding (an index of 5-HT transporter (5-HTT) expression) was only slightly affected by Org 34850 alone: decreased in cortex and midbrain and increased in hippocampus. In contrast, chronic fluoxetine markedly decreased 5-HTT levels in all regions. Importantly, this decrease was significantly enhanced by combined Org 34850/fluoxetine treatment. There were no changes in the expression of 5-HTT mRNA, suggesting these effects were not due to changes in gene transcription. Expression of tryptophan hydroxylase mRNA and both 5-HT(1A) autoreceptor mRNA and protein (assessed using [(3)H]-8-OH-DPAT binding) were unchanged by any treatment. The expression of postsynaptic 5-HT(1A) receptor protein in the forebrain was unaltered by fluoxetine, Org 34850 or the combined Org 34850/fluoxetine treatment. This downregulation of 5-HTT by fluoxetine and its enhancement by Org 34850 can explain our recent observation that GR antagonists augment the SSRI-induced increase in extracellular 5-HT. In addition, these data suggest that the augmentation of forebrain 5-HT does not result in downregulation of forebrain 5-HT(1A) receptor expression. Given the importance of 5-HT(1A) receptor-mediated transmission in the forebrain to the antidepressant response, these data indicate that co-administration of GR antagonists may be effective in augmenting the antidepressant response to SSRI treatment.

摘要

研究了糖皮质激素受体(GR)拮抗剂Org 34850与选择性5-羟色胺再摄取抑制剂(SSRI)氟西汀联合治疗对5-羟色胺(5-HT)神经传递突触前和突触后方面的影响。用Org 34850(每天15毫克/千克皮下注射)、氟西汀(每天10毫克/千克腹腔注射)或两种药物的组合对大鼠进行14天的治疗。[(3)H]-西酞普兰结合(5-羟色胺转运体(5-HTT)表达的指标)仅受Org 34850单独轻微影响:在皮质和中脑降低,在海马体中增加。相比之下,慢性氟西汀显著降低了所有区域的5-HTT水平。重要的是,Org 34850/氟西汀联合治疗显著增强了这种降低。5-HTT mRNA的表达没有变化,表明这些作用不是由于基因转录的变化。色氨酸羟化酶mRNA以及5-HT(1A)自身受体mRNA和蛋白质的表达(使用[(3)H]-8-OH-DPAT结合评估)在任何治疗下均未改变。氟西汀、Org 34850或Org 34850/氟西汀联合治疗对前脑突触后5-HT(1A)受体蛋白的表达没有改变。氟西汀对5-HTT的这种下调及其被Org 34850增强可以解释我们最近的观察结果,即GR拮抗剂增强了SSRI诱导的细胞外5-HT增加。此外,这些数据表明前脑5-HT的增加不会导致前脑5-HT(1A)受体表达的下调。鉴于前脑5-HT(1A)受体介导的传递对抗抑郁反应的重要性,这些数据表明GR拮抗剂的联合给药可能有效地增强对SSRI治疗的抗抑郁反应。

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