Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany.
Eur J Pharmacol. 2010 May 10;633(1-3):33-8. doi: 10.1016/j.ejphar.2010.01.016. Epub 2010 Feb 1.
The transcription factor CREB regulates adaptive responses like memory consolidation, addiction, and synaptic refinement. Recently, chronic psychosocial stress as animal model of depression has been shown to stimulate CREB transcriptional activity in the brain; this stimulation was prevented by treatment with the antidepressant imipramine, which inhibits both noradrenaline and serotonin reuptake. However, it was unknown whether the selective inhibition of serotonin reuptake is sufficient for inhibition of stress-induced CREB activation, as it is for the clinical antidepressant effect. Therefore, the effect of two selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, was examined in this study. Transgenic CRE-luciferase reporter gene mice were used to monitor gene transcription directed by the CREB DNA binding site (CRE) in vivo. Chronic psychosocial stress for 25days stimulated CRE/CREB-directed luciferase expression in the hippocampus and other brain regions. When applied alone to non-stressed mice, citalopram caused a transient increase after 24h that was lost after 21days of treatment, whereas fluoxetine had no effect after 24h and produced an inhibition in the pons and hypothalamus after 21days of treatment. However, both citalopram and fluoxetine treatment completely abolished the increase in CRE/CREB-directed transcription induced by chronic psychosocial stress. As indicated by Western blots, the changes in CRE/CREB-directed transcription were accompanied by corresponding changes in the phosphorylation of CREB at serine-119. These results further emphasize the role of CREB in stress-induced gene expression and suggest furthermore that inhibition of stress-induced CREB activity may be a common mechanism of action of SSRIs underlying their antidepressive effect.
转录因子 CREB 调节适应性反应，如记忆巩固、成瘾和突触细化。最近，作为抑郁症动物模型的慢性心理社会应激已被证明会刺激大脑中的 CREB 转录活性；这种刺激可被抗抑郁药丙咪嗪（同时抑制去甲肾上腺素和 5-羟色胺再摄取）治疗所阻止。然而，尚不清楚选择性抑制 5-羟色胺再摄取是否足以抑制应激诱导的 CREB 激活，就像它对临床抗抑郁作用一样。因此，本研究检查了两种选择性 5-羟色胺再摄取抑制剂（SSRIs）西酞普兰和氟西汀的作用。使用转基因 CRE-荧光素酶报告基因小鼠来监测体内由 CREB DNA 结合位点（CRE）指导的基因转录。慢性心理社会应激 25 天刺激了海马体和其他脑区的 CRE/CREB 指导的荧光素酶表达。当单独应用于未应激的小鼠时，西酞普兰在 24 小时后引起短暂增加，但在 21 天治疗后消失，而氟西汀在 24 小时后没有作用，在 21 天治疗后在脑桥和下丘脑产生抑制。然而，西酞普兰和氟西汀治疗完全消除了慢性心理社会应激引起的 CRE/CREB 指导的转录增加。如 Western blot 所示，CRE/CREB 指导的转录变化伴随着 CREB 在丝氨酸 119 处磷酸化的相应变化。这些结果进一步强调了 CREB 在应激诱导基因表达中的作用，并进一步表明抑制应激诱导的 CREB 活性可能是 SSRIs 抗抑郁作用的共同作用机制。
Zotero 插件