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Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation

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Abstract

Introduction

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, 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).

Discussion

This demonstration replicates the fluoxetine-induced cPLA2 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-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, 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).

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References

  • Baez M, Kursar JD, Helton LA, Wainscott DB, Nelson DL (1995) Molecular biology of serotonin receptors. Obes Res 3(Suppl 4):441S–447S

    CAS  PubMed  Google Scholar 

  • Balboa MA, Balsinde J (2002) Involvement of calcium-independent phospholipase A2 in hydrogen peroxide-induced accumulation of free fatty acids in human U937 cells. J Biol Chem 277:40384–40389

    Article  CAS  PubMed  Google Scholar 

  • Bazan NG (2005) Lipid signaling in neural plasticity, brain repair, and neuroprotection. Mol Neurobiol 32:89–103

    Article  CAS  PubMed  Google Scholar 

  • Benfield P, Heel RC, Lewis SP (1986) Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32:481–508

    Article  CAS  PubMed  Google Scholar 

  • Beyer CE, Cremers TI (2008) Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin? Eur J Pharmacol 580:350–354

    Article  CAS  PubMed  Google Scholar 

  • Bolo NR, Hode Y, Nedelec JF, Laine E, Wagner G, Macher JP (2000) Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacology 23:428–438

    Article  CAS  PubMed  Google Scholar 

  • Bonaventure P, Nepomuceno D, Kwok A et al (2002) Reconsideration of 5-hydroxytryptamine (5-HT)(7) receptor distribution using [(3)H]5-carboxamidotryptamine and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline: analysis in brain of 5-HT(1A) knockout and 5-HT(1A/1B) double-knockout mice. J Pharmacol Exp Ther 302:240–248

    Article  CAS  PubMed  Google Scholar 

  • Bonhaus DW, Bach C, DeSouza A et al (1995) The pharmacology and distribution of human 5-hydroxytryptamine2B (5-HT2B) receptor gene products: comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol 115:622–628

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Buchsbaum MS, Wu J, Siegel BV et al (1997) Effect of sertraline on regional metabolic rate in patients with affective disorder. Biol Psychiatry 41:15–22

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Peng L, Zhang X, Stolzenburg JU, Hertz L (1995) Further evidence that fluoxetine interacts with a 5-HT2C receptor in glial cells. Brain Res Bull 38:153–159

    Article  CAS  PubMed  Google Scholar 

  • Choi DS, Maroteaux L (1996) Immunohistochemical localisation of the serotonin 5-HT2B receptor in mouse gut, cardiovascular system, and brain. FEBS Lett 391:45–51

    Article  CAS  PubMed  Google Scholar 

  • Doly S, Valjent E, Setola V et al (2008) Serotonin 5-HT2B receptors are required for 3, 4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. J Neurosci 28:2933–2940

    Article  CAS  PubMed  Google Scholar 

  • Elizabeth Sublette ME, Milak MS et al (2009) Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression. Prostaglandins Leukot Essent Fat Acids 80:57–64

    Article  CAS  Google Scholar 

  • El-Marjou M, Montalescot V, Buzyn A, Geny B (2000) Modifications in phospholipase D activity and isoform expression occur upon maturation and differentiation in vivo and in vitro in human myeloid cells. Leukemia 14:2118–2127

    Article  CAS  PubMed  Google Scholar 

  • Favata MF, Horiuchi KY, Manos EJ et al (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    Article  CAS  PubMed  Google Scholar 

  • Felder CC, Kanterman RY, Ma AL, Axelrod J (1990) Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc Natl Acad Sci U S A 87:2187–2191

    Article  CAS  PubMed  Google Scholar 

  • Ferguson JM, Hill H (2006) Pharmacokinetics of fluoxetine in elderly men and women. Gerontology 52:45–50

    Article  CAS  PubMed  Google Scholar 

  • Fiacco TA, McCarthy KD (2006) Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia 54:676–690

    Article  PubMed  Google Scholar 

  • Garcia MC, Kim HY (1997) Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Brain Res 768:43–48

    Article  CAS  PubMed  Google Scholar 

  • Hansson E, Rönnbäck L (2004) Astrocytic receptors and second messenger systems. In: Hertz L (ed) Non-neuronal cells of the nervous system, function and dysfunction. Elsevier, Amsterdam, pp 475–501

    Google Scholar 

  • Hansson E, Simonsson P, Alling C (1987) 5-Hydroxytryptamine stimulates the formation of inositol phosphate in astrocytes from different regions of the brain. Neuropharmacology 26:1377–1382

    Article  CAS  PubMed  Google Scholar 

  • Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031

    Article  CAS  PubMed  Google Scholar 

  • Henry ME, Schmidt ME, Hennen J et al (2005) A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: a 19-F MRS study. Neuropsychopharmacology 30:1576–1583

    Article  CAS  PubMed  Google Scholar 

  • Hertz L (2008) Bioenergetics of cerebral ischemia: a cellular perspective. Neuropharmacology 55:289–309

    Article  CAS  PubMed  Google Scholar 

  • Hertz L, Baldwin F, Schousboe A (1979) Serotonin receptors on astrocytes in primary cultures: effects of methysergide and fluoxetine. Can J Physiol Pharmacol 57:223–226

    CAS  PubMed  Google Scholar 

  • Hertz L, Juurlin BHJ, Szuchet S (1985) Cell cultures. In: Lajtha A (ed) Handbook of Neurochemistry Vol 8, 2nd edn. Plenum Press, New York, pp 603–661

    Google Scholar 

  • Hertz L, Bender AS, Woodbury DM, White HS (1989) Potassium-stimulated calcium uptake in astrocytes and its potent inhibition by nimodipine. J Neurosci Res 22:209–215

    Article  CAS  PubMed  Google Scholar 

  • Hertz L, Peng L, Lai JC (1998) Functional studies in cultured astrocytes. Methods 16:293–310

    Article  CAS  PubMed  Google Scholar 

  • Ivanov AI, Pero RS, Scheck AC, Romanovsky AA (2002) Prostaglandin E(2)-synthesizing enzymes in fever: differential transcriptional regulation. Am J Physiol Regul Integr Comp Physiol 283:R1104–R1117

    PubMed  Google Scholar 

  • Jerman JC, Brough SJ, Gager T et al (2001) Pharmacological characterisation of human 5-HT2 receptor subtypes. Eur J Pharmacol 414:23–30

    Article  CAS  PubMed  Google Scholar 

  • Kennedy BP, Payette P, Mudgett J et al (1995) A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J Biol Chem 270:22378–22385

    Article  CAS  PubMed  Google Scholar 

  • Kimbrell TA, Ketter TA, George MS et al (2002) Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biol Psychiatry 51:237–252

    Article  CAS  PubMed  Google Scholar 

  • Kong EK, Peng L, Chen Y, Yu AC, Hertz L (2002) Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration. Neurochem Res 27:113–120

    Article  CAS  PubMed  Google Scholar 

  • Kursar JD, Nelson DL, Wainscott DB, Baez M (1994) Molecular cloning, functional expression, and mRNA tissue distribution of the human 5-hydroxytryptamine2B receptor. Mol Pharmacol 46:227–234

    CAS  PubMed  Google Scholar 

  • Lautens LL, Chiou XG, Sharp JD et al (1998) Cytosolic phospholipase A2 (cPLA2) distribution in murine brain and functional studies indicate that cPLA2 does not participate in muscarinic receptor-mediated signaling in neurons. Brain Res 809:18–30

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Rao JS, Chang L, Rapoport SI, Bazinet RP (2008) Chronic N-methyl-d-aspartate administration increases the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat. J Lipid Res 49:162–168

    Article  CAS  PubMed  Google Scholar 

  • Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788

    Article  CAS  PubMed  Google Scholar 

  • Levy DE, Lapierre F, Liang W et al (1998) Matrix metalloproteinase inhibitors: a structure-activity study. J Med Chem 41:199–223

    Article  CAS  PubMed  Google Scholar 

  • Li B, Gu L, Zhang H et al (2007) Up-regulation of cPLA(2) gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific. Psychopharmacology (Berl) 194:333–345

    Article  CAS  Google Scholar 

  • Li B, Du T, Li H et al (2008a) Signalling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br J Pharmacol 154:191–203

    Article  CAS  PubMed  Google Scholar 

  • Li B, Zhang S, Zhang H et al (2008b) Fluoxetine-mediated 5-HT(2B) receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation. Psychopharmacology (Berl) 201:443–458

    Article  CAS  Google Scholar 

  • Lindbom J, Ljungman AG, Lindahl M, Tagesson C (2001) Expression of members of the phospholipase A2 family of enzymes in human nasal mucosa. Eur Respir J 18:130–138

    Article  CAS  PubMed  Google Scholar 

  • Little JT, Ketter TA, Kimbrell TA et al (1996) Venlafaxine or bupropion responders but not nonresponders show baseline prefrontal and paralimbic hypometabolism compared with controls. Psychopharmacol Bull 32:629–635

    CAS  PubMed  Google Scholar 

  • Little JT, Ketter TA, Kimbrell TA et al (2005) Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression. Biol Psychiatry 57:220–228

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Smith BJ, Chen C et al (2005) Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood–brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther 313:1254–1262

    Article  CAS  PubMed  Google Scholar 

  • Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L (1989) Fluoxetine treatment of depression. Clinical effects, drug concentrations and monoamine metabolites and N-terminally extended substance P in cerebrospinal fluid. Acta Psychiatr Scand 79:586–596

    Article  CAS  PubMed  Google Scholar 

  • Mayberg HS, Brannan SK, Tekell JL et al (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843

    Article  CAS  PubMed  Google Scholar 

  • Mercier G, Lennon AM, Renouf B et al (2004) MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci 24:207–216

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH, Kapur S, Eisfeld B et al (2001) The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. Am J Psychiatry 158:78–85

    Article  CAS  PubMed  Google Scholar 

  • Milak MS, Parsey RV et al (2009) Pretreatment regional brain glucose uptake in the midbrain on PET may predict remission from a major depressive episode after three months of treatment. Psychiatry Res 173:63–70

    Article  CAS  PubMed  Google Scholar 

  • New AS, Buchsbaum MS, Hazlett EA et al (2004) Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression. Psychopharmacology (Berl) 176:451–458

    Article  CAS  Google Scholar 

  • Nierenberg AA, Farabaugh AH, Alpert JE et al (2000) Timing of onset of antidepressant response with fluoxetine treatment. Am J Psychiatry 157:1423–1428

    Article  CAS  PubMed  Google Scholar 

  • Nilsson M, Hansson E, Ronnback L (1991) Adrenergic and 5-HT2 receptors on the same astroglial cell. A microspectrofluorimetric study on cytosolic Ca2+ responses in single cells in primary culture. Brain Res Dev Brain Res 63:33–41

    Article  CAS  PubMed  Google Scholar 

  • Ong WY, Sandhya TL, Horrocks LA, Farooqui AA (1999) Distribution of cytoplasmic phospholipase A2 in the normal rat brain. J Hirnforsch 39:391–400

    PubMed  Google Scholar 

  • Pardue S, Rapoport SI, Bosetti F (2003) Co-localization of cytosolic phospholipase A2 and cyclooxygenase-2 in rhesus monkey cerebellum. Brain Res Mol Brain Res 116:106–114

    Article  CAS  PubMed  Google Scholar 

  • Poblete JC, Azmitia EC (1995) Activation of glycogen phosphorylase by serotonin and 3, 4-methylenedioxymethamphetamine in astroglial-rich primary cultures: involvement of the 5-HT2A receptor. Brain Res 680:9–15

    Article  CAS  PubMed  Google Scholar 

  • Qi X, Lin W, Li J et al (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285

    Article  CAS  PubMed  Google Scholar 

  • Qu Y, Chang L, Klaff J, Seemann R, Rapoport SI (2003) Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. Neuropsychopharmacology 28:1219–1226

    Article  CAS  PubMed  Google Scholar 

  • Qu Y, Chang L, Klaff J, Seemann R, Greenstein D, Rapoport SI (2006) Chronic fluoxetine upregulates arachidonic acid incorporation into the brain of unanesthetized rats. Eur Neuropsychopharmacol 16:561–571

    Article  CAS  PubMed  Google Scholar 

  • Rao JS, Ertley RN, Lee HJ, Rapoport SI, Bazinet RP (2006) Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex. Pharmacogenomics J 6:413–420

    Article  CAS  PubMed  Google Scholar 

  • Rapoport SI (2008) Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fat Acids 79:153–156

    Article  CAS  Google Scholar 

  • Rasgon NL, Kenna HA, Geist C, Small G, Silverman D (2008) Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder. Psychiatry Res 164:77–80

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL (2000) Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102:2836–2841

    CAS  PubMed  Google Scholar 

  • Sandén N, Thorlin T, Blomstrand F, Persson PA, Hansson E (2000) 5-Hydroxytryptamine2B receptors stimulate Ca2+ increases in cultured astrocytes from three different brain regions. Neurochem Int 36:427–434

    Article  PubMed  Google Scholar 

  • Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H (1996) Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? Eur J Neurosci 8:959–967

    Article  CAS  PubMed  Google Scholar 

  • Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (2003) 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol 63:1223–1229

    Article  CAS  PubMed  Google Scholar 

  • Sorg O, Pellerin L, Stolz M, Beggah S, Magistretti PJ (1995) Adenosine triphosphate and arachidonic acid stimulate glycogenolysis in primary cultures of mouse cerebral cortical astrocytes. Neurosci Lett 188:109–112

    Article  CAS  PubMed  Google Scholar 

  • Stout BD, Clarke WP, Berg KA (2002) Rapid desensitization of the serotonin(2C) receptor system: effector pathway and agonist dependence. J Pharmacol Exp Ther 302:957–962

    Article  CAS  PubMed  Google Scholar 

  • Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022

    Article  CAS  PubMed  Google Scholar 

  • Sun GY, Xu J, Jensen MD, Simonyi A (2004) Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45:205–213

    Article  CAS  PubMed  Google Scholar 

  • Tay A, Maxwell P, Li ZG, Goldberg H, Skorecki K (1994) Cytosolic phospholipase A2 gene expression in rat mesangial cells is regulated post-transcriptionally. Biochem J 304:417–422

    CAS  PubMed  Google Scholar 

  • Videbech P (2000) PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 101:11–20

    Article  CAS  PubMed  Google Scholar 

  • Yu PH, Hertz L (1982) Differential expression of type A and type B monoamine oxidase of mouse astrocytes in primary cultures. J Neurochem 39:1493–1495

    Google Scholar 

  • Yu PH, Hertz L (1983) Type A and B monoamine oxidase in glial cells in long term culture. Prog Neuropsychopharmacol Biol Psychiatry 7:687–690

    Article  CAS  PubMed  Google Scholar 

  • Yu AC, Lee YL, Eng LF (1993) Astrogliosis in culture: I. The model and the effect of antisense oligonucleotides on glial fibrillary acidic protein synthesis. J Neurosci Res 34:295–303

    Article  CAS  PubMed  Google Scholar 

  • Zhao Z, Hertz L, Code WE (1996) Effects of benzodiazepines on potassium-induced increase in free cytosolic calcium concentration in astrocytes: interactions with nifedipine and the peripheral-type benzodiazepine antagonist PK 11195. Can J Physiol Pharmacol 74:273–277

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grant numbers 30670651, 30770667, and 30711120572 from the National Natural Science Foundation of China.

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  1. Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, No. 92 Beier Road, Heping District, Shenyang, People’s Republic of China

    Baoman Li, Shiquen Zhang, Min Li, Leif Hertz & Liang Peng

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  1. Baoman Li
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Li, B., Zhang, S., Li, M. et al. Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation. Psychopharmacology 207, 1–12 (2009). https://doi.org/10.1007/s00213-009-1631-3

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