Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA₂ expression secondary to 5-HT_2B-induced, transactivation-mediated ERK_1/2 phosphorylation

摘要

Introduction We have recently shown that fluoxetine, a serotonin-specific reuptake inhibitor (SSRI), has low micromolar affinity for the 5-HT_2C receptor (but not for 5-HT_2A and 5-HT_2B receptors) in primary cultures of mouse astrocytes. This was determined as phosphorylation (stimulation) of extracellular-regulated kinase 1 and 2 (ERK_1/2) by transactivation-mediated phosphorylation of the epidermal growth factor (EGF) receptor, followed by conventional EGF receptor signaling (Li et al., Psychopharmacology 194:333–334, 2007). Paroxetine has an identical effect. The present study shows that chronic fluoxetine treatment with even higher affinity (EC₅₀ = 0.5–2.0 µM) upregulates Ca2+-dependent phospholipase A₂ (cPLA₂), which releases arachidonic acid from the sn-2 position of membrane-bound phospholipid, without effect on secretory PLA₂ (sPLA₂) and intracellular PLA₂ (iPLA₂).