Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface.
Work in our laboratory has focused on the mechanisms by which cytokines can influence the brain and behavior in humans and non-human primates. Using administration of interferon (IFN)-alpha as a tool to unravel these mechanisms, we have expanded upon findings from the basic science literature implicating cytokine-induced changes in monoamine metabolism as a primary pathway to depression. More specifically, a role for serotonin metabolism has been supported by the clinical efficacy of serotonin reuptake inhibitors in blocking the development of IFN-alpha-induced depression, and the capacity of IFN-alpha to activate metabolic enzymes (indolamine 2,3 dioxygenase) and cytokine signaling pathways (p38 mitogen activated protein kinase) that can influence the synthesis and reuptake of serotonin. Our data also support a role for dopamine depletion as reflected by IFN-alpha-induced changes in behavior (psychomotor slowing and fatigue) and regional brain activity, which implicate the involvement of the basal ganglia, as well as the association of IFN-alpha-induced depressive-like behavior in rhesus monkeys with decreased cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid. Neuroimaging data in IFN-alpha-treated patients also suggest that activation of neural circuits (dorsal anterior cingulate cortex) associated with anxiety and alarm may contribute to cytokine-induced behavioral changes. Taken together, these effects of cytokines on the brain and behavior appear to subserve competing evolutionary survival priorities that promote reduced activity to allow healing, and hypervigilance to protect against future attack. Depending on the relative balance between these behavioral accoutrements of an activated innate immune response, clinical presentations may be distinct and warrant individualized therapeutic approaches.
Miller
Andrew H
AH
Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, 1701 Uppergate Drive, WCI Building C, 5th Floor, Atlanta, GA 30322, USA. amill02@emory.edu
D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D001519:Behavior / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D003863:Depression / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology*; D004298:Dopamine / Q000134:cerebrospinal fluid; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage / Q000276:immunology*; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D004298:Dopamine; D006719:Homovanillic Acid; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
Atherosclerosis. 2007 Dec;195(2):e10-8
17669411
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1920-5
12578963
Biol Psychiatry. 2006 May 1;59(9):775-85
16458261
Mol Psychiatry. 2010 May;15(5):535-47
18521089
N Engl J Med. 1999 Apr 29;340(17):1370
10223879
Brain Behav Immun. 2007 May;21(4):374-83
17360153
Arch Gen Psychiatry. 2008 Apr;65(4):409-15
18391129
Biol Psychiatry. 2003 Nov 1;54(9):906-14
14573318
Neuroreport. 2001 Dec 21;12(18):4121-5
11742250
J Immunother. 2007 Apr;30(3):333-7
17414324
Arch Gen Psychiatry. 2005 Nov;62(11):1228-36
16275810
Mol Psychiatry. 2007 Oct;12(10):895-7
17895923
Am J Psychiatry. 2006 Sep;163(9):1630-3
16946190
Am J Psychiatry. 2001 Feb;158(2):314-6
11156819
Mol Psychiatry. 2001 Jul;6(4):475-80
11443537
Comput Med Imaging Graph. 1995 May-Jun;19(3):295-306
7641174
Neurology. 2004 Oct 26;63(8 Suppl 3):S2-7
15505137
Gen Hosp Psychiatry. 1999 Mar-Apr;21(2):134-5
10228895
Circulation. 2003 Jan 28;107(3):363-9
12551853
Brain Behav Immun. 2008 Aug;22(6):870-80
18258414
Neurology. 2001 Dec 11;57(11):2083-8
11739830
N Engl J Med. 2001 Mar 29;344(13):961-6
11274622
J Neuropsychiatry Clin Neurosci. 2005 Spring;17(2):185-91
15939972
Neuropathol Appl Neurobiol. 2005 Aug;31(4):395-404
16008823
Biol Psychiatry. 2002 Oct 1;52(7):740-8
12372665
J Neuroimmunol. 2007 Feb;183(1-2):125-32
17229471
Neuroimmunomodulation. 1995 Jul-Aug;2(4):216-23
8963750
J Clin Psychiatry. 2005 Jan;66(1):41-8
15669887
J Neurosci. 2003 Sep 17;23(24):8480-8
13679416
J Neurochem. 2004 Oct;91(1):220-9
15379902
Neuroscience. 1991;41(1):1-24
1676137
Eur Neuropsychopharmacol. 2000 Mar;10(2):129-32
10706995
Neuropsychopharmacology. 2008 Jun;33(7):1503-13
17882235
J Neural Transm Gen Sect. 1993;91(2-3):75-109
8099801
Science. 2003 Jul 18;301(5631):386-9
12869766
Arch Gen Psychiatry. 1992 Jun;49(6):447-50
1376107
Brain Res. 1996 Mar 4;711(1-2):163-74
8680860
Biol Psychiatry. 1994 Jan 15;35(2):128-32
8167208
J Neurol Sci. 2000 Oct 1;179(S 1-2):34-42
11054483
Ann Neurol. 1990 Jul;28(1):57-64
2375634
Psychol Sci. 2003 Jul;14(4):347-53
12807408
Cogn Affect Behav Neurosci. 2005 Jun;5(2):169-81
16180623
CNS Drugs. 2005;19(2):105-23
15697325
J Clin Psychiatry. 2005 Aug;66(8):1050-7
16086622
Annu Rev Neurosci. 2007;30:259-88
17600522
Arch Gen Psychiatry. 2007 Mar;64(3):327-37
17339521
Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11-38
7708925
J Neurosci. 1995 Jan;15(1 Pt 1):376-84
7823142
Trends Cogn Sci. 2004 Jul;8(7):294-300
15242688
Science. 1998 May 1;280(5364):747-9
9563953
Pharmacol Biochem Behav. 1992 May;42(1):57-60
1528947
Vet Clin North Am Small Anim Pract. 1991 Mar;21(2):225-37
2053246
Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S203-6
14677080
Brain Behav Immun. 2007 Feb;21(2):153-60
17088043
Science. 1972 Mar 24;175(4028):1380-2
5059569
Adv Neurol. 2003;91:9-18
12442660
Psychosom Med. 2001 May-Jun;63(3):376-86
11382265
Clin Neuropathol. 2001 Jul-Aug;20(4):146-55
11495003
Nature. 1999 Aug 12;400(6745):621-2
10458157
Brain Res. 2003 Jul 18;978(1-2):104-14
12834904
Fed Proc. 1985 Jan;44(1 Pt 2):249-53
3871411
Biol Psychiatry. 2005 Aug 1;58(3):190-6
16084839
Psychol Med. 1997 Nov;27(6):1247-56
9403896
J Neurovirol. 1999 Oct;5(5):500-6
10568887
Lancet. 2006 Jan 7;367(9504):29-35
16399150
Dis Nerv Syst. 1971 Nov;32(11):735-41
5002259
Trends Immunol. 2006 Jan;27(1):24-31
16316783
Mov Disord. 2001 Mar;16(2):190-6
11295769
J Pharmacol Exp Ther. 1988 Mar;244(3):1067-80
2855239
Neurosci Biobehav Rev. 1992 Winter;16(4):525-34
1480349
J Neural Transm (Vienna). 2007 Jan;114(1):33-41
16932989
Neuropsychopharmacology. 2006 Oct;31(10):2121-31
16452991
World J Biol Psychiatry. 2007;8(3):141-74
17654407
Brain Behav Immun. 1997 Jun;11(2):107-18
9299060
Arch Gen Psychiatry. 2001 May;58(5):445-52
11343523
Neurosci Lett. 2006 Apr 24;397(3):254-8
16406668
J Clin Psychiatry. 2006;67 Suppl 6:3-8
16848670
Biochem Pharmacol. 2006 Nov 30;72(11):1605-21
16889756
Mol Psychiatry. 2002;7(5):468-73
12082564
Nat Rev Neurosci. 2008 Jan;9(1):46-56
18073775
Mov Disord. 2003 Oct;18(10):1108-14
14534913
Biol Psychiatry. 2004 Jun 15;55(12):1179-87
15184037
J Pharmacol Exp Ther. 2003 Apr;305(1):1-8
12649346
J Cereb Blood Flow Metab. 1994 Sep;14(5):783-801
8063874
Life Sci. 2000 Jun 30;67(6):663-9
12659172
Aliment Pharmacol Ther. 2007 May 15;25(10):1163-74
17451562
Biol Psychiatry. 1992 Jan 15;31(2):112-8
1371076
J Biol Chem. 2005 Apr 22;280(16):15649-58
15728187
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1319-24
17229839
Clin Neuropharmacol. 2000 Jan-Feb;23(1):59-61
10682234
Curr Opin Pharmacol. 2005 Feb;5(1):34-41
15661623
Oncol Nurs Forum. 2002 Aug;29(7):E85-90
12183762
Psychol Rev. 1998 Jan;105(1):83-107
9450372
Am J Psychiatry. 2002 May;159(5):746-54
11986127
Biol Psychiatry. 2004 Dec 1;56(11):819-24
15576057
Ann N Y Acad Sci. 2003 Jun;991:199-213
12846988
Am J Psychiatry. 2003 Jul;160(7):1342-5
12832253
Psychosomatics. 2000 Sep-Oct;41(5):439-41
11015632
Mol Psychiatry. 2005 Jun;10(6):538-44
15494706
J Biol Chem. 2007 Mar 16;282(11):7783-9
17227768
J Neuroinflammation. 2005 Jul 26;2:16
16042813
Neurosci Lett. 2005 Feb 28;375(2):107-11
15670651
J Neurochem. 2002 Jun;81(6):1285-97
12068076
Prog Neurobiol. 1997 Feb;51(2):195-222
9247964
Mol Psychiatry. 2007 Nov;12(11):988-1000
17457312
Psychopharmacology (Berl). 2000 Nov;152(4):383-9
11140330
Mol Psychiatry. 2007 Apr;12(4):408-17
17389906
Eur Heart J. 2002 Jun;23(11):831-4
12042000
Brain Res. 1997 Feb 7;747(2):348-51
9046014
Curr Pharm Des. 2005;11(8):999-1016
15777250
J Psychopharmacol. 2000;14(3):214-21
11106299
J Neurochem. 2003 Aug;86(3):774-83
12859689
Psychopharmacology (Berl). 1996 Jul;126(1):91-4
8853222
Mol Psychiatry. 2009 May;14(5):511-22
18195714
Annu Rev Neurosci. 1986;9:357-81
3085570
Neuropsychopharmacology. 2002 May;26(5):643-52
11927189
Neurosci Lett. 1995 Apr 14;189(2):73-6
7609922
Neuropsychopharmacology. 2007 Nov;32(11):2384-92
17327884
Brain Behav Immun. 2001 Sep;15(3):199-226
11566046
Arch Neurol. 2000 Nov;57(11):1601-7
11074792
Mol Psychiatry. 2009 Dec;14(12):1095-104
18458677
J Affect Disord. 2000 Jul;59(1):23-30
10814767
Biol Psychiatry. 2007 Dec 1;62(11):1324-33
17678633
Brain Behav Immun. 1995 Dec;9(4):366-77
8903853
Behav Brain Res. 2006 Nov 25;175(1):90-5
16971003