title: Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling.
abstract: Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3β (GSK3β) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3β signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France [4] Université Paris Descartes, Ecole Doctorale Médicament Toxicologie Chimie Environnement, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Couroussé
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Bacq
authors.affiliation: INSERM U930, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Belzung
authors.affiliation: Laboratoire de Neuropharmacologie EA3544, Université Paris-Sud XI, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: B
authors.initials: B
authors.lastname: Guiard
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Balasse
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Louis
authors.affiliation: INSERM U930, Tours, France.
authors.forename: A-M
authors.initials: AM
authors.lastname: Le Guisquet
authors.affiliation: Laboratoire de Neuropharmacologie EA3544, Université Paris-Sud XI, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: A M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France [4] Douglas Hospital, Department of Psychiatry, McGill University, Montreal, QC, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Giros
authors.affiliation: 1] INSERM U1130, Paris, France [2] CNRS UMR 8246, Paris, France [3] Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Gautron
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002908:Chronic Disease; D003345:Corticosterone / Q000008:administration & dosage / Q000378:metabolism; D003863:Depression / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006728:Hormones / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D055500:Resilience, Psychological; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D035501:Uncertainty
chemical_list: D006728:Hormones; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse; D012701:Serotonin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D003345:Corticosterone; D009638:Norepinephrine
references.citation: Neuropharmacology. 2013 Jan;64:65-73
references.pmid: 22732443
references.citation: PLoS One. 2008;3(10):e3540
references.pmid: 18958152
references.citation: Nature. 2008 Oct 16;455(7215):894-902
references.pmid: 18923511
references.citation: Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2460-74
references.pmid: 22826345
references.citation: Nat Neurosci. 2012 Nov;15(11):1475-84
references.pmid: 23064380
references.citation: Front Mol Neurosci. 2011 Oct 24;4:31
references.pmid: 22028682
references.citation: J Pharmacol Exp Ther. 2001 Mar;296(3):987-95
references.pmid: 11181933
references.citation: Nat Neurosci. 2007 Nov;10(11):1401-3
references.pmid: 17906620
references.citation: Nat Rev Neurosci. 2008 Mar;9(3):182-94
references.pmid: 18270514
references.citation: J Neurochem. 2008 Aug;106(3):1471-82
references.pmid: 18513366
references.citation: Mol Cell Biol. 2003 Nov;23(21):7902-8
references.pmid: 14560032
references.citation: Integr Comp Biol. 2002 Jul;42(3):541-51
references.pmid: 21708749
references.citation: Neurobiol Dis. 2013 Apr;52:12-23
references.pmid: 22659304
references.citation: Front Neuroendocrinol. 2003 Jul;24(3):151-80
references.pmid: 14596810
references.citation: Neuron. 2002 Mar 28;34(1):13-25
references.pmid: 11931738
references.citation: Am J Psychiatry. 2000 Jun;157(6):896-903
references.pmid: 10831468
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1333-8
references.pmid: 18212115
references.citation: J Neurosci. 2004 Jul 28;24(30):6791-8
references.pmid: 15282284
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):397-409
references.pmid: 19469025
references.citation: Br J Pharmacol. 2002 Jul;136(6):829-36
references.pmid: 12110607
references.citation: J Neurosci. 2011 Jun 22;31(25):9084-92
references.pmid: 21697359
references.citation: Ann N Y Acad Sci. 2004 Jun;1018:65-70
references.pmid: 15240353
references.citation: Am J Psychiatry. 2010 May;167(5):509-27
references.pmid: 20231323
references.citation: Biol Psychiatry. 2008 Feb 15;63(4):353-9
references.pmid: 17889834
references.citation: Neurobiol Learn Mem. 2012 Sep;98(2):122-9
references.pmid: 22800848
references.citation: J Pharmacol Exp Ther. 2000 Feb;292(2):684-91
references.pmid: 10640306
references.citation: Nature. 1998 Aug 20;394(6695):787-90
references.pmid: 9723618
references.citation: Biol Psychiatry. 2004 Apr 15;55(8):781-4
references.pmid: 15050857
references.citation: J Neurosci. 2006 Aug 23;26(34):8758-66
references.pmid: 16928864
references.citation: J Neurosci. 2010 Nov 10;30(45):15185-95
references.pmid: 21068324
references.citation: Annu Rev Pharmacol Toxicol. 2009;49:327-47
references.pmid: 18928402
references.citation: J Clin Psychiatry. 1996 Oct;57(10):470-84
references.pmid: 8909334
references.citation: Curr Protoc Pharmacol. 2013 Jun;Chapter 5:Unit 5.65
references.pmid: 23744712
references.citation: Behav Brain Res. 2010 Apr 2;208(2):553-9
references.pmid: 20060021
references.citation: Mol Endocrinol. 2003 Aug;17(8):1640-6
references.pmid: 12764077
references.citation: Nature. 2011 Jan 27;469(7331):491-7
references.pmid: 21270887
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16697-702
references.pmid: 20823230
references.citation: Br J Pharmacol. 2001 Oct;134(3):585-95
references.pmid: 11588113
references.citation: Neuron. 2007 Mar 1;53(5):703-17
references.pmid: 17329210
references.citation: J Pharmacol Exp Ther. 2002 Mar;300(3):918-24
references.pmid: 11861798
references.citation: Neuroscience. 2010 Sep 1;169(3):1216-26
references.pmid: 20576499
references.citation: Physiol Rev. 2009 Apr;89(2):535-606
references.pmid: 19342614
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):434-45
references.pmid: 19401723
references.citation: Nat Rev Neurosci. 2012 Nov;13(11):769-87
references.pmid: 23047775
references.citation: Nat Neurosci. 2010 Nov;13(11):1351-3
references.pmid: 20890295
references.citation: Mol Pharmacol. 1998 Aug;54(2):342-52
references.pmid: 9687576
references.citation: Nat Protoc. 2006;1(3):1117-9
references.pmid: 17406392
references.citation: Biol Psychiatry. 2008 Aug 15;64(4):293-301
references.pmid: 18406399
references.citation: Mol Pharmacol. 2008 Nov;74(5):1463-75
references.pmid: 18703671
references.citation: Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86
references.pmid: 16272756
references.citation: Annu Rev Neurosci. 2003;26:299-330
references.pmid: 12598680
references.citation: Pharmacol Rev. 1996 Dec;48(4):495-530
references.pmid: 8981564
references.citation: Eur J Pharmacol. 2010 Jan 10;626(1):83-6
references.pmid: 19835870
references.citation: J Clin Psychiatry. 2000;61 Suppl 5:24-9; discussion 30-2
references.pmid: 10761676
references.citation: Front Mol Neurosci. 2012 Feb 09;5:4
references.pmid: 22363258
references.citation: J Neurosci. 2013 Feb 27;33(9):3857-64
references.pmid: 23447597
references.citation: Mol Psychiatry. 2012 Sep;17(9):926-39
references.pmid: 21769100
references.citation: Neuropsychopharmacology. 2004 Aug;29(8):1426-31
references.pmid: 15039769
references.citation: Nat Rev Neurosci. 2001 May;2(5):343-51
references.pmid: 11331918
references.citation: Br J Pharmacol. 2003 Nov;140(6):1128-36
references.pmid: 14530210
references.citation: Cell. 2008 Jan 11;132(1):125-36
references.pmid: 18191226
references.citation: Science. 2012 Mar 23;335(6075):1510-3
references.pmid: 22362879
references.citation: J Neurosci. 2013 Jun 19;33(25):10534-43
references.pmid: 23785165
references.citation: Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2395-401
references.pmid: 22826340
references.citation: Trends Neurosci. 1997 Feb;20(2):78-84
references.pmid: 9023876
references.citation: Neuropsychopharmacology. 2010 Jul;35(8):1761-74
references.pmid: 20357757
references.citation: Nat Neurosci. 1998 Sep;1(5):349-51
references.pmid: 10196521
references.citation: Mol Cell. 2001 Jun;7(6):1321-7
references.pmid: 11430833
references.citation: Psychol Med. 2013 Mar;43(3):449-69
references.pmid: 22564216
references.citation: Trends Neurosci. 2008 Sep;31(9):464-8
references.pmid: 18675469