Abstract
The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Affect / drug effects*
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Affect / physiology
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Analysis of Variance
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Animals
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Antidepressive Agents / pharmacology*
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Antidiuretic Hormone Receptor Antagonists
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Cytostatic Agents / pharmacology
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Depression / drug therapy*
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Depression / etiology
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Drug Combinations
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Fluoxetine / pharmacology
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Hippocampus / cytology
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Hippocampus / drug effects*
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Hippocampus / physiology
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Imipramine / pharmacology
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Indoles / pharmacology
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Male
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Methylazoxymethanol Acetate / analogs & derivatives
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Methylazoxymethanol Acetate / pharmacology
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Mitosis / drug effects
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Neurogenesis / drug effects
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Neurogenesis / physiology
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Neuronal Plasticity / drug effects*
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Neuronal Plasticity / physiology
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Prefrontal Cortex / cytology
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / physiology
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Pyrrolidines / pharmacology
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Rats
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Rats, Wistar
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Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
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Stress, Psychological / complications
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Stress, Psychological / physiopathology
Substances
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1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide
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Antidepressive Agents
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Antidiuretic Hormone Receptor Antagonists
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Cytostatic Agents
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Drug Combinations
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Indoles
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Pyrrolidines
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Receptors, Corticotropin-Releasing Hormone
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Fluoxetine
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Methylazoxymethanol Acetate
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methylazoxymethanol
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Imipramine