Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation.
BACKGROUND
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 (EC(50) = 0.5-2.0 microM) upregulates Ca(2+)-dependent phospholipase A(2) (cPLA(2)), which releases arachidonic acid from the sn-2 position of membrane-bound phospholipid, without effect on secretory PLA(2) (sPLA(2)) and intracellular PLA(2) (iPLA(2)).


CONCLUSIONS
This demonstration replicates the fluoxetine-induced cPLA(2) upregulation in rat brain shown by Rao et al. (Pharmacogenomics J 6:413-420, 2006) and provides the new information that upregulation (1) occurs in astrocytes, (2) is evoked by stimulation of 5-HT(2B) receptor, and (3) requires transactivation-mediated ERK(1/2) phosphorylation. Similar upregulation of cPLA(2) in intact brain in response to 5-HT(2)-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, 1993) 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, 2009).
Li
Baoman
B
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, No. 92 Beier Road, Heping District, Shenyang, People's Republic of China.
Zhang
Shiquen
S
Li
Min
M
Hertz
Leif
L
Peng
Liang
L
D000818:Animals; D001253:Astrocytes; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005473:Fluoxetine; D007211:Indoles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054467:Phospholipases A2; D012333:RNA, Messenger; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D014508:Urea; C092756:N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea