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We have recently shown that fluoxetine, a serotonin-specific reuptake inhibitor (SSRI), has low micromolar affinity for the 5-HT2C receptor (but not for 5-HT2A and 5-HT2B receptors) in primary cultures of mouse astrocytes. This was determined as phosphorylation (stimulation) of extracellular-regulated kinase 1 and 2 (ERK1/2) by transactivation-mediated phosphorylation of the epidermal growth factor (EGF) receptor, followed by conventional EGF receptor signaling (Li et al., Psychopharmacology 194:333–334, ). 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). This demonstration replicates the fluoxetine-induced cPLA2 upregulation in rat brain shown by Rao et al. (Pharmacogenomics J 6:413–420, ) and provides the new information that upregulation (1) occurs in astrocytes, (2) is evoked by stimulation of 5-HT2B receptor, and (3) requires transactivation-mediated ERK1/2 phosphorylation. Similar upregulation of cPLA2 in intact brain in response to 5-HT2-mediated signaling by elevated serotonin levels and/or an SSRI during antidepressant treatment may explain the repeatedly reported ability of SSRIs to normalize regional decreases which occur in brain metabolism during major depression, since (1) arachidonic acid strongly stimulates glucose metabolism in cultured astrocytes (Yu et al., J Neurosci Res 64:295–303, ) and (2) plasma concentrations of arachidonic acid in depressed patients are linearly correlated with regional brain glucose metabolism (Elizabeth Sublette et al., Prostaglandins Leukot Essent Fatty Acids 80:57–64, ). [ABSTRACT FROM AUTHOR]