Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression.

Full Abstract

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.

Author information

Author/s: Haenisch, Britta (B); Bilkei-Gorzo, Andras (A); Caron, Marc G (MG); Bönisch, Heinz (H);

Affiliation: Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany. boenisch(-atsign-)uni-bonn.de

Grants: P50 MH060451 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2009-Oct; vol 111 (issue 2) : pp 403-16

Dates: Created 2009/09/29; Completed 2009/10/22;

PMID: 19694905, status: MEDLINE (last retrieval date: 10/22/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Antidepressive Agents - pharmacology
Behavior, Animal - drug effects; physiology
Brain Stem - physiology
Brain-Derived Neurotrophic Factor - genetics
Cerebellum - physiology
Chronic Disease
Depressive Disorder - drug therapy; physiopathology
Disease Models, Animal
Female
Male
Mice

Associated Chemicals: Antidepressive Agents (0) ; Brain-Derived Neurotrophic Factor (0) ; Nerve Growth Factors (0) ; Norepinephrine Plasma Membrane Transport Proteins (0) ; RNA, Messenger (0) ; Slc6a2 protein, mouse (0) ; neurotropin 3, mouse (0) ; Nerve Growth Factor (9061-61-4)

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