Johnson Daniel Anthony, Ingram Colin David, Grant Emma Jane, Craighead Mark, Gartside Sarah Elizabeth
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
Neuropsychopharmacology. 2009 Jan;34(2):399-409. doi: 10.1038/npp.2008.70. Epub 2008 May 21.
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.
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。