Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression.
Diverse factors such as changes in neurotrophins and brain plasticity have been proposed to be involved in the actions of antidepressant drugs (ADs). However, in mouse models of depression based on chronic stress, it is still unclear whether simultaneous changes in behavior and neurotrophin expression occur and whether these changes can be corrected or prevented comparably by chronic administration of ADs or genetic manipulations that produce antidepressant-like effects such as the knockout of the norepinephrine transporter (NET) gene. Here we show that chronic restraint or social defeat stress induce comparable effects on behavior and changes in the expression of neurotrophins in depression-related brain regions. Chronic stress caused down-regulation of BDNF, nerve growth factor, and neurotrophin-3 in hippocampus and cerebral cortex and up-regulation of these targets in striatal regions. In wild-type mice, these effects could be prevented by concomitant chronic administration of five pharmacologically diverse ADs. In contrast, NET knock out (NETKO) mice were resistant to stress-induced depressive-like changes in behavior and brain neurotrophin expression. Thus, the resistance of the NETKO mice to the stress-induced depression-associated behaviors and biochemical changes highlight the importance of noradrenergic pathways in the maintenance of mood. In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants.
Haenisch
Britta
B
Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. boenisch@uni-bonn.de
Bilkei-Gorzo
Andras
A
Caron
Marc G
MG
Bönisch
Heinz
H
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001933:Brain Stem / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002531:Cerebellum / Q000502:physiology; D002908:Chronic Disease; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D009830:Olfactory Bulb / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012149:Restraint, Physical; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology; D013550:Swimming
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493228:Slc6a2 protein, mouse; C518911:neurotropin 3, mouse; D020932:Nerve Growth Factor
Mol Psychiatry. 2000 Sep;5(5):510-3
11032384
Neuropsychopharmacology. 2003 Mar;28(3):421-34
12629522
Nature. 2008 Oct 16;455(7215):894-902
18923511
Nat Neurosci. 2006 Sep;9(9):1134-41
16906152
Neuropsychopharmacology. 2006 Nov;31(11):2424-32
16554743
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8788-92
7568018
J Neurosci. 1995 Nov;15(11):7539-47
7472505
Nat Neurosci. 2007 Sep;10(9):1110-5
17726477
Biol Psychiatry. 2006 Feb 1;59(3):244-51
16140276
Nat Rev Drug Discov. 2005 Sep;4(9):775-90
16138108
Horm Behav. 2006 Nov;50(4):529-33
16901485
Life Sci. 2003 Feb 14;72(13):1437-44
12535712
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2259-60
18272485
Biol Psychiatry. 2003 Nov 15;54(10):994-1005
14625141
Handb Exp Pharmacol. 2006;(175):485-524
16722247
J Neural Transm (Vienna). 2008 Jul;115(7):973-82
18335160
Synapse. 2003 Oct;50(1):77-82
12872296
J Neurosci. 2000 Dec 15;20(24):9104-10
11124987
Behav Brain Res. 2007 Apr 16;179(1):1-18
17306892
Biol Psychiatry. 2003 Apr 15;53(8):707-42
12706957
Mol Neurobiol. 1996 Dec;13(3):185-97
8989769
Curr Opin Pharmacol. 2007 Feb;7(1):18-21
17049922
Int J Neuropsychopharmacol. 2008 Aug;11(5):625-39
18205979
Biol Psychiatry. 2006 Jun 15;59(12):1151-9
16566899
Brain Res. 2001 Dec 13;922(1):9-20
11730697
Science. 2006 Feb 10;311(5762):864-8
16469931
J Neurochem. 1995 Apr;64(4):1585-97
7891086
Eur Arch Psychiatry Clin Neurosci. 1996;246(5):235-9
8863001
Front Biosci. 2006 May 01;11:1794-801
16368556
Neuroscience. 2006;139(3):931-46
16515844
Neurosci Biobehav Rev. 2008;32(3):508-24
18023876
CNS Drugs. 2008;22(1):15-26
18072812
Brain Res. 1981 Jan 5;204(1):1-11
6166350
Int Clin Psychopharmacol. 2003 Jul;18(4):191-202
12817153
Behav Pharmacol. 2008 Sep;19(5-6):566-74
18690111
J Psychiatr Res. 2008 Oct;42(14):1145-53
18313696
Nat Neurosci. 2001 Jan;4(1):29-37
11135642
Biol Psychiatry. 2006 Jun 15;59(12):1116-27
16631126
Nat Rev Neurosci. 2005 Jun;6(6):463-75
15891777
Eur J Neurosci. 2008 Sep;28(5):883-92
18717734
Neuropharmacology. 1999 Feb;38(2):299-306
10218872
J Physiol Pharmacol. 2005 Dec;56(4):661-71
16391422
Neuropsychopharmacology. 2007 Apr;32(4):822-34
16841072
Nature. 1977 Apr 21;266(5604):730-2
559941
Neuropsychopharmacology. 1999 Aug;21(2):268-84
10432475
Am J Psychiatry. 2007 Dec;164(12):1790
18056232
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10827-32
15249684
Biol Psychiatry. 2008 Aug 15;64(4):293-301
18406399
Neurosci Res. 2008 May;61(1):106-12
18329744
Synapse. 2001 Dec 15;42(4):203-12
11746719
J Neurosci Res. 2006 Feb 15;83(3):497-507
16416425
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6227-32
12732720
Exp Neurol. 2006 Dec;202(2):404-9
16914143
Brain Res. 2008 May 23;1211:37-43
18433734
J Psychiatry Neurosci. 2001;26 Suppl:S3-10
11590967
Psychopharmacology (Berl). 1991;104(2):255-9
1876670
Eur Neuropsychopharmacol. 2007 Feb;17(3):215-26
16997535
Neuropsychopharmacology. 2007 Oct;32(10):2152-62
17314919
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Depress Anxiety. 2000;12 Suppl 1:2-19
11098410
Neuropharmacology. 1980 Apr;19(4):355-63
6104308
Pharmacol Biochem Behav. 2006 Apr;83(4):592-7
16712910
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12796-801
11675510
Nat Neurosci. 2000 May;3(5):465-71
10769386
Biol Psychiatry. 1999 Nov 1;46(9):1124-30
10560019
Nat Rev Neurosci. 2006 Feb;7(2):137-51
16429123
Biol Psychiatry. 2008 Apr 1;63(7):640-1
18329441
Br J Pharmacol. 1995 Jun;115(4):703-11
7582494
Biochem Biophys Res Commun. 2007 Mar 2;354(1):284-9
17222806