Cell type-specific gene expression and editing responses to chronic fluoxetine treatment in the in vivo mouse brain and their relevance for stress-induced anhedonia.
Recently developed methods for fluorescence-activated cell sorting (FACS) of freshly-isolated brain cells from transgenic mice combining fluorescent signals with cell type-specific markers allow cell-type separation. Based upon previous observations in primary cultures of mouse astrocytes we treated transgenic mice tagged with a neuron-specific or an astrocyte-specific marker with fluoxetine, either acute (10 mg/kg for 2 h) or chronic (10 mg/kg daily for 2 weeks). Acute treatment upregulated cfos and fosB mRNA expression in astrocytes and neurons. Chronic effects on astrocytes replicated those demonstrated in cultures, i.e., upregulation of mRNA and/or protein expression of 5-HT(2B) receptors (5-HT(2B)R), and GluK2 receptors, and of cPLA(2a) and ADAR2, together with increased GluK2 and 5-HT(2B)R editing. Neurons showed increased GluK4 and 5-HT(2C) receptor expression. To further correlate these findings with major depression we compared the changes in gene expression with those in a mouse model of anhedonia. Three out of 4 genes up-regulated in astrocytes by fluoxetine were down-regulated, whereas the neuronally upregulated 5-HT(2C) receptor gene showed no change. References are made to recent review papers discussing potential relations between observed fluoxetine effects and clinical effects of SSRIs, emphasizing that all 5 clinically used SSRIs have identical and virtually equipotent effects on cultured astrocytes.
Department of Clinical Pharmacology and Institute of Pathophysiology, China Medical University, No. 92 Beier Road, Heping District, Shenyang, People's Republic of China. baoman801226@yahoo.com.cn
Baoman
B
Li
Lu
L
Dong
Bing
B
Wang
Liping
L
Cai
Ning
N
Jiang
Liang
L
Peng
D059445:Anhedonia; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D005473:Fluoxetine / Q000494:pharmacology*; D015870:Gene Expression; D008297:Male; D051379:Mice; D054467:Phospholipases A2 / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013312:Stress, Physiological
D017931:DNA Primers; D005473:Fluoxetine; D054467:Phospholipases A2; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044348:Receptors, Serotonin, 5-HT2; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors