Sillaber Inge, Panhuysen Markus, Henniger Markus S H, Ohl Frauke, Kühne Claudia, Pütz Benno, Pohl Thomas, Deussing Jan M, Paez-Pereda Marcelo, Holsboer Florian
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
Psychopharmacology (Berl). 2008 Nov;200(4):557-72. doi: 10.1007/s00213-008-1232-6. Epub 2008 Jul 16.
Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition.
To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression.
The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology.
Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice.
Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.
基于单胺的抗抑郁药在短时间内抑制神经递质再摄取。然而，通常需要数周临床症状才开始缓解，这表明存在与再摄取抑制无关的效应。
为了揭示药物作用的其他机制，采用“反向”药理学方法来确定抗抑郁药引起的海马基因表达变化。
通过强迫游泳试验（FST）、改良洞板试验（mHB）和明暗箱试验评估雄性DBA/2Ola小鼠长期服用帕罗西汀后的行为反应。解剖未进行过试验的小鼠的海马体，采用微阵列技术研究帕罗西汀治疗引起的基因表达变化。
观察到帕罗西汀对FST中被动应激应对行为有显著影响。此外，在DBA小鼠的mHB试验和明暗箱试验中均发现长期抗抑郁治疗具有抗焦虑特性。微阵列结果分析显示，慢性帕罗西汀治疗可使60个基因的表达发生差异调节。前脑啡肽原1和抑制素β - A的转录变化水平最高。此外，还出现了一些与神经可塑性/神经发生相关的候选基因（如Bdnf、Gfap、Vim、Sox11、Egr1、Stat3）。通过原位杂交证实了7个选定的候选基因。GFAP和波形蛋白的额外免疫荧光共定位研究表明，在长期接受帕罗西汀治疗的DBA小鼠中可检测到更多阳性细胞。
我们认为，本研究中使用对长期帕罗西汀治疗有反应的小鼠品系鉴定出的候选基因，有助于阐明帕罗西汀作为选择性5-羟色胺再摄取抑制剂（SSRI）代表药物的作用机制。
