title: 5-HT2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional 'serotonin-specific reuptake inhibitors'.
abstract: In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the 'serotonin-specific reuptake inhibitor' (SSRI) fluoxetine leads acutely to 5-HT2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) with an EC50 of ~5 μM, and chronically to ERK1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A2 (cPLA2) with ten-fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK1/2 and mRNA and protein expression of cPLA2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT2 receptor, the 5-HT2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA2a expression during chronic treatment; citalopram had a similar effect at 0.1-0.5 μM; these are therapeutically relevant concentrations.
authors.affiliation: Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China.
authors.forename: Shiquen
authors.initials: S
authors.lastname: Zhang
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.forename: Ditte
authors.initials: D
authors.lastname: Lovatt
authors.forename: Junnan
authors.initials: J
authors.lastname: Xu
authors.forename: Dan
authors.initials: D
authors.lastname: Song
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
authors.forename: Leif
authors.initials: L
authors.lastname: Hertz
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D005434:Flow Cytometry / Q000379:methods; D005473:Fluoxetine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017374:Paroxetine / Q000494:pharmacology; D044403:Receptor, Serotonin, 5-HT2B / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D005473:Fluoxetine; D017374:Paroxetine; D044403:Receptor, Serotonin, 5-HT2B; D017367:Selective Serotonin Reuptake Inhibitors