Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.

Full Abstract

Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Author information

Author/s: David, Denis J (DJ); Samuels, Benjamin Adam (BA); Rainer, Quentin (Q); Wang, Jing-Wen (JW); Marsteller, Douglas (D); Mendez, Indira (I); Drew, Michael (M); Craig, Douglas A (DA); Guiard, Bruno P (BP); Guilloux, Jean-Philippe (JP); Artymyshyn, Roman P (RP); Gardier, Alain M (AM); Gerald, Christophe (C); Antonijevic, Irina A (IA); Leonardo, E David (ED); Hen, René (R);

Affiliation: Université Paris-Sud EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex F-92296, France. denis.david(-atsign-)u-psud.fr

Grants: 1K99MH083943-01 (Agency:NIMH NIH HHS) ; 5-T32HD55165-02 (Agency:NICHD NIH HHS) ; 5K08MH076083 (Agency:NIMH NIH HHS) ; R01 MH068542 (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: Neuron (Neuron), published in United States. (Language: eng)

Reference: 2009-May; vol 62 (issue 4) : pp 479-93

Dates: Created 2009/05/29; Completed 2009/06/15; Revised 2009/10/09;

PMID: 19477151, status: MEDLINE (last retrieval date: 10/12/2009, IMS Date: 12 Oct 2009 00:00:00)

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

Comments and Corrections

CommentIn: Neuron. 2009 May 28;62(4):453-5. (PMID: 19477146)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Analysis of Variance
Animals
Antidepressive Agents, Second-Generation - therapeutic use
Anxiety - chemically induced; diet therapy; pathology
Arrestins - deficiency; genetics; metabolism
Bromodeoxyuridine - metabolism
Cell Proliferation - drug effects; radiation effects
Cell Survival - drug effects; radiation effects
Corticosterone - toxicity
Depression - chemically induced; drug therapy; pathology
Disease Models, Animal
Drug Administration Schedule
Exploratory Behavior - drug effects
Feeding Behavior - drug effects
Fluoxetine - therapeutic use

Fluoxetine - therapeutic use
GTP-Binding Protein alpha Subunit, Gi2 - genetics; metabolism
Gene Expression Regulation - drug effects; genetics; radiation effects
Hippocampus - drug effects; pathology; radiation effects
Hypothalamus - drug effects; metabolism; radiation effects
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microtubule-Associated Proteins - metabolism
Neurogenesis - drug effects; radiation effects
Neuropeptides - metabolism
RNA, Messenger - metabolism
Radiation
Reaction Time - drug effects

Associated Chemicals: Antidepressive Agents, Second-Generation (0) ; Arrestins (0) ; Microtubule-Associated Proteins (0) ; Neuropeptides (0) ; RNA, Messenger (0) ; beta-arrestin (0) ; doublecortin protein (0) ; Corticosterone (50-22-6) ; Fluoxetine (54910-89-3) ; Bromodeoxyuridine (59-14-3) ; GTP-Binding Protein alpha Subunit, Gi2 (EC 3.6.1.46)

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