Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression.
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.
David
Denis J
DJ
Université Paris-Sud EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex F-92296, France. denis.david@u-psud.fr
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
D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001007:Anxiety / Q000139:chemically induced / Q000178:diet therapy* / Q000473:pathology; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003345:Corticosterone / Q000633:toxicity; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000627:therapeutic use*; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000528:radiation effects; D009479:Neuropeptides / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011827:Radiation; D011930:Reaction Time / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
D018687:Antidepressive Agents, Second-Generation; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D005473:Fluoxetine; D051960:GTP-Binding Protein alpha Subunit, Gi2; D001973:Bromodeoxyuridine; D003345:Corticosterone