PMID- 19694905 OWN - NLM STAT- MEDLINE DCOM- 20091022 LR - 20211020 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 111 IP - 2 DP - 2009 Oct TI - Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression. PG - 403-16 LID - 10.1111/j.1471-4159.2009.06345.x [doi] AB - 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. FAU - Haenisch, Britta AU - Haenisch B AD - Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. boenisch@uni-bonn.de FAU - Bilkei-Gorzo, Andras AU - Bilkei-Gorzo A FAU - Caron, Marc G AU - Caron MG FAU - Bonisch, Heinz AU - Bonisch H LA - eng GR - P50 MH060451/MH/NIMH NIH HHS/United States GR - P50 MH060451-090004/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20090818 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Growth Factors) RN - 0 (Norepinephrine Plasma Membrane Transport Proteins) RN - 0 (RNA, Messenger) RN - 0 (Slc6a2 protein, mouse) RN - 0 (neurotropin 3, mouse) RN - 9061-61-4 (Nerve Growth Factor) SB - IM MH - Animals MH - Antidepressive Agents/*pharmacology MH - Behavior, Animal/drug effects/physiology MH - Brain Stem/physiology MH - Brain-Derived Neurotrophic Factor/genetics MH - Cerebellum/physiology MH - Chronic Disease MH - Depressive Disorder/*drug therapy/*physiopathology MH - Disease Models, Animal MH - Female MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nerve Growth Factor/genetics MH - Nerve Growth Factors/genetics MH - Norepinephrine Plasma Membrane Transport Proteins/*genetics/*metabolism MH - Olfactory Bulb/physiology MH - RNA, Messenger/metabolism MH - Restraint, Physical MH - Social Behavior MH - Stress, Psychological/physiopathology MH - Swimming PMC - PMC2764285 MID - NIHMS145805 EDAT- 2009/08/22 09:00 MHDA- 2009/10/23 06:00 PMCR- 2010/10/01 CRDT- 2009/08/22 09:00 PHST- 2009/08/22 09:00 [entrez] PHST- 2009/08/22 09:00 [pubmed] PHST- 2009/10/23 06:00 [medline] PHST- 2010/10/01 00:00 [pmc-release] AID - JNC6345 [pii] AID - 10.1111/j.1471-4159.2009.06345.x [doi] PST - ppublish SO - J Neurochem. 2009 Oct;111(2):403-16. doi: 10.1111/j.1471-4159.2009.06345.x. Epub 2009 Aug 18.