Abstract
Rationale
The pharmacological actions of most antidepressants are ascribed to the modulation of serotonergic and/or noradrenergic transmission in the brain. During therapeutic treatment for major depression, fluoxetine, one of the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, accumulates in the brain, suggesting that fluoxetine may interact with additional targets. In this context, there is increasing evidence that astrocytes are involved in the pathophysiology of major depression.
Objectives
The aim of this study was to examine the effects of fluoxetine on the expression of neurotrophic/growth factors that have antidepressant properties and on glucose metabolism in cultured cortical astrocytes.
Results
Treatment of astrocytes with fluoxetine and paroxetine, another SSRI antidepressant, upregulated brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and VGF mRNA expression. In contrast, the tricyclic antidepressants desipramine and imipramine did not affect the expression of these neurotrophic/growth factors. Analysis of the effects of fluoxetine on glucose metabolism revealed that fluoxetine reduces glycogen levels and increases glucose utilization and lactate release by astrocytes. Similar data were obtained with paroxetine, whereas imipramine and desipramine did not regulate glucose metabolism in this glial cell population. Our results also indicate that the effects of fluoxetine and paroxetine on glucose utilization, lactate release, and expression of BDNF, VEGF, and VGF are not mediated by serotonin-dependent mechanisms.
Conclusions
These data suggest that, by increasing the expression of specific astrocyte-derived neurotrophic factors and lactate release from astrocytes, fluoxetine may contribute to normalize the trophic and metabolic support to neurons in major depression.
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References
Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, Shors TJ, Black IB (2003) Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 23:10800–10808
Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30:3326–3338
Allaman I, Pellerin L, Magistretti PJ (2004) Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes. J Neurochem 88:900–908
Allen NJ, Barres BA (2005) Signaling between glia and neurons: focus on synaptic plasticity. Curr Opin Neurobiol 15:542–548
Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64:863–870
Barker AJ, Ullian EM (2010) Astrocytes and synaptic plasticity. Neuroscientist 16:40–50
Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151
Bianchi MT (2008) Non-serotonin anti-depressant actions: direct ion channel modulation by SSRIs and the concept of single agent poly-pharmacy. Med Hypotheses 70:951–956
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
Bonni A, Ginty DD, Dudek H, Greenberg ME (1995) Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Mol Cell Neurosci 6:168–183
Bremner JD, Vythilingam M, Vermetten E, Nazeer A, Adil J, Khan S, Staib LH, Charney DS (2002) Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 51:273–279
Brown AM, Ransom BR (2007) Astrocyte glycogen and brain energy metabolism. Glia 55:1263–1271
Cater HL, Benham CD, Sundstrom LE (2001) Neuroprotective role of monocarboxylate transport during glucose deprivation in slice cultures of rat hippocampus. J Physiol 531:459–466
Cattaneo A, Sesta A, Calabrese F, Nielsen G, Riva MA, Gennarelli M (2010) The expression of VGF is reduced in leukocytes of depressed patients and it is restored by effective antidepressant treatment. Neuropsychopharmacology 35:1423–1428
Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265
Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE Jr, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 102:15653–15658
Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394
Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31:1616–1626
Drevets WC (2000a) Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126:413–431
Drevets WC (2000b) Neuroimaging studies of mood disorders. Biol Psychiatry 48:813–829
Drevets WC (2001) Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 11:240–249
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003) Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60:804–815
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676
Furutani K, Ohno Y, Inanobe A, Hibino H, Kurachi Y (2009) Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel. Mol Pharmacol 75:1287–1295
Ghosh A, Carnahan J, Greenberg ME (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263:1618–1623
Greene J, Banasr M, Lee B, Warner-Schmidt J, Duman RS (2009) Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment: pharmacological and cellular characterization. Neuropsychopharmacology 34:2459–2468
Guo S, Arai K, Stins MF, Chuang DM, Lo EH (2009) Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke 40:652–655
Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355
Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62:1310–1316
Henry ME, Schmidt ME, Hennen J, Villafuerte RA, Butman ML, Tran P, Kerner LT, Cohen B, Renshaw PF (2005) A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: a 19-F MRS study. Neuropsychopharmacology 30:1576–1583
Hisaoka K, Takebayashi M, Tsuchioka M, Maeda N, Nakata Y, Yamawaki S (2007) Antidepressants increase glial cell line-derived neurotrophic factor production through monoamine-independent activation of protein tyrosine kinase and extracellular signal-regulated kinase in glial cells. J Pharmacol Exp Ther 321:148–157
Hoshaw BA, Malberg JE, Lucki I (2005) Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 1037:204–208
Hunsberger JG, Newton SS, Bennett AH, Duman CH, Russell DS, Salton SR, Duman RS (2007) Antidepressant actions of the exercise-regulated gene VGF. Nat Med 13:1476–1482
Jin K, Mao XO, Greenberg DA (2006) Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J Neurobiol 66:236–242
Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950
Jones KR, Farinas I, Backus C, Reichardt LF (1994) Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76:989–999
Khaibullina AA, Rosenstein JM, Krum JM (2004) Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. Brain Res Dev Brain Res 148:59–68
Khawaja X, Xu J, Liang JJ, Barrett JE (2004) Proteomic analysis of protein changes developing in rat hippocampus after chronic antidepressant treatment: implications for depressive disorders and future therapies. J Neurosci Res 75:451–460
Krum JM, Mani N, Rosenstein JM (2002) Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience 110:589–604
Lewin GR, Barde YA (1996) Physiology of the neurotrophins. Annu Rev Neurosci 19:289–317
Lindholm D, Carroll P, Tzimagiogis G, Thoenen H (1996) Autocrine-paracrine regulation of hippocampal neuron survival by IGF-1 and the neurotrophins BDNF, NT-3 and NT-4. Eur J Neurosci 8:1452–1460
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408
Magistretti PJ (2008) Brain energy metabolism. In: Squire LR, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer NC (eds) Fundamental neuroscience, 3rd edn. Academic Press, San Diego, pp 271–293
Magistretti PJ, Manthorpe M, Bloom FE, Varon S (1983) Functional receptors for vasoactive intestinal polypeptide in cultured astroglia from neonatal rat brain. Regul Pept 6:71–80
Magistretti PJ, Sorg O, Martin JL (1993) Regulation of glycogen metabolism in astrocytes: physiological, pharmacological, and pathological aspects. In: Murphy S (ed) Astrocytes: pharmacology and function. Academic Press, San Diego, pp 243–265
Malberg JE, Monteggia LM (2008) VGF, a new player in antidepressant action? Sci Signal 1:e19
Mallei A, Shi B, Mocchetti I (2002) Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons. Mol Pharmacol 61:1017–1024
Maus M, Marin P, Israel M, Glowinski J, Premont J (1999) Pyruvate and lactate protect striatal neurons against N-methyl-D-aspartate-induced neurotoxicity. Eur J Neurosci 11:3215–3224
Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843
McAllister AK, Katz LC, Lo DC (1996) Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17:1057–1064
McAllister AK, Lo DC, Katz LC (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15:791–803
Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 23:10841–10851
Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547
Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95:13290–13295
Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: An update. Glia 55:1251–1262
Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431
Rajkowska G (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 48:766–777
Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6:219–233
Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098
Rosenstein JM, Mani N, Khaibullina A, Krum JM (2003) Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons. J Neurosci 23:11036–11044
Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322:1551–1555
Salton SR, Ferri GL, Hahm S, Snyder SE, Wilson AJ, Possenti R, Levi A (2000) VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. Front Neuroendocrinol 21:199–219
Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF (2004) Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713
Schurr A, Payne RS, Miller JJ, Rigor BM (1997a) Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem 69:423–426
Schurr A, Payne RS, Miller JJ, Rigor BM (1997b) Glia are the main source of lactate utilized by neurons for recovery of function posthypoxia. Brain Res 774:221–224
Sheline YI (2003) Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 54:338–352
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261
Si X, Miguel-Hidalgo JJ, O'Dwyer G, Stockmeier CA, Rajkowska G (2004) Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology 29:2088–2096
Sickmann HM, Walls AB, Schousboe A, Bouman SD, Waagepetersen HS (2009) Functional significance of brain glycogen in sustaining glutamatergic neurotransmission. J Neurochem 109(Suppl 1):80–86
Slezak M, Pfrieger FW (2003) New roles for astrocytes: regulation of CNS synaptogenesis. Trends Neurosci 26:531–535
Thakker-Varia S, Alder J (2009) Neuropeptides in depression: role of VGF. Behav Brain Res 197:262–278
Thakker-Varia S, Krol JJ, Nettleton J, Bilimoria PM, Bangasser DA, Shors TJ, Black IB, Alder J (2007) The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus. J Neurosci 27:12156–12167
Turner CA, Gula EL, Taylor LP, Watson SJ, Akil H (2008) Antidepressant-like effects of intracerebroventricular FGF2 in rats. Brain Res 1224:63–68
Wada T, Haigh JJ, Ema M, Hitoshi S, Chaddah R, Rossant J, Nagy A, van der Kooy D (2006) Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival. J Neurosci 26:6803–6812
Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86:342–367
Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci USA 104:4647–4652
Warner-Schmidt JL, Duman RS (2008) VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 8:14–19
Wong DT, Perry KW, Bymaster FP (2005) Case history: the discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov 4:764–774
Wong ML, Licinio J (2004) From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov 3:136–151
Zhang X, Peng L, Chen Y, Hertz L (1993) Stimulation of glycogenolysis in astrocytes by fluoxetine, an antidepressant acting like 5-HT. NeuroReport 4:1235–1238
Acknowledgments
The authors are grateful to Cendrine Barrière Borgioni and Evelyne Ruchti for valuable technical assistance. This work was supported by the Swiss National Science Foundation grants 31003A-124783 (to JLM) and 3100AO-108336/1 (to PJM), the Désirée and Niels Yde's Foundation (to JLM and PJM), and the Swiss Academy of Medical Sciences (to JLM and PJM). The authors have no financial relationship with the Swiss National Science Foundation, the Désirée and Niels Yde's Foundation, and the Swiss Academy of Medical Sciences. All experiments comply with the Swiss federal act on animal protection and the Swiss animal protection ordinance.
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Allaman, I., Fiumelli, H., Magistretti, P.J. et al. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology 216, 75–84 (2011). https://doi.org/10.1007/s00213-011-2190-y
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DOI: https://doi.org/10.1007/s00213-011-2190-y