Dong Lu, Li Baoman, Verkhratsky Alexei, Peng Liang
Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, People's Republic of China.
Psychopharmacology (Berl). 2015 Aug;232(15):2827-35. doi: 10.1007/s00213-015-3921-2. Epub 2015 Apr 9.
Previously, we reported that chronic treatment with fluoxetine increased gene expression of 5-hydroxytryptamine receptor 2B (5-HT2BR), cytosolic phospholipase 2α (cPLA2α), glutamate receptor, ionotropic kainate 2 (GluK2) and adenosine deaminase acting on RNA 2 (ADAR2), in cultured astrocytes and astrocytes freshly isolated from transgenic mice tagged with an astrocyte-specific marker. In contrast, neurones isolated from transgenic mice tagged with a neurone-specific marker and exposed to fluoxetine showed an increase in gene expression of glutamate receptor, ionotropic kainate 4 (GluK4) and 5-hydroxytryptamine receptor 2C (5-HT2CR). In a mouse model of anhedonia, the downregulation of 5-HT2BR, cPLA2α, ADAR2 and GluK4 but not GluK2 and 5-HT2CR was detected.
To investigate the effects of chronic mild stress (CMS) and/or fluoxetine treatment on gene expression of 5-HT2BR, 5-HT2CR, cPLA2α, ADAR2, GluK2 and GluK4 specifically in astrocytes and neurones.
Transgenic mice tagged with either astrocyte- or neurone-specific markers were exposed to the CMS. Real-time PCR was applied to determine expression of messenger RNA (mRNA).
We found that (i) mRNAs of the 5-HT2BR and cPLA2α in astrocytes and GluK4 in neurones were significantly reduced in mice that became anhedonic; the mRNA levels were restored by fluoxetine treatment; (ii) ADAR2 in astrocytes was decreased by the CMS but showed no response to fluoxetine in anhedonic animals; (iii) neither GluK2 expression in astrocytes nor 5-HT2CR expression in neurones were affected in anhedonic animals, although expression of 5-HT2CR mRNA was upregulated by fluoxetine.
Our results indicate that the effects of chronic treatment with fluoxetine are not only dependent on the cell type studied but also on the development of anhedonia. This suggests that fluoxetine may affect major depression (MD) patients and healthy people in a different manner.
此前，我们报道过，在培养的星形胶质细胞以及从带有星形胶质细胞特异性标记的转基因小鼠中新鲜分离出的星形胶质细胞中，长期使用氟西汀进行治疗会增加5-羟色胺受体2B（5-HT2BR）、胞质磷脂酶2α（cPLA2α）、谷氨酸受体、离子型红藻氨酸受体2（GluK2）和作用于RNA的腺苷脱氨酶2（ADAR2）的基因表达。相反，从带有神经元特异性标记的转基因小鼠中分离出并暴露于氟西汀的神经元，其谷氨酸受体、离子型红藻氨酸受体4（GluK4）和5-羟色胺受体2C（5-HT2CR）的基因表达增加。在快感缺失的小鼠模型中，检测到5-HT2BR、cPLA2α、ADAR2和GluK4的下调，但GluK2和5-HT2CR未下调。
研究慢性轻度应激（CMS）和/或氟西汀治疗对5-HT2BR、5-HT2CR、cPLA2α、ADAR2、GluK2和GluK4基因表达的影响，具体针对星形胶质细胞和神经元。
将带有星形胶质细胞或神经元特异性标记的转基因小鼠暴露于CMS。应用实时聚合酶链反应（PCR）来测定信使核糖核酸（mRNA）的表达。
我们发现：（i）在出现快感缺失的小鼠中，星形胶质细胞中的5-HT2BR和cPLA2α的mRNA以及神经元中的GluK4的mRNA显著降低；氟西汀治疗可使mRNA水平恢复；（ii）CMS使星形胶质细胞中的ADAR2减少，但在快感缺失的动物中，ADAR2对氟西汀无反应；（iii）快感缺失的动物中，星形胶质细胞中的GluK2表达和神经元中的5-HT2CR表达均未受影响，不过氟西汀可上调5-HT2CR mRNA的表达。
我们的结果表明，长期使用氟西汀进行治疗的效果不仅取决于所研究的细胞类型，还取决于快感缺失的发展情况。这表明氟西汀可能以不同方式影响重度抑郁症（MD）患者和健康人群。
