title: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.
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.
authors.affiliation: Life and Health Science Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: J M
authors.initials: JM
authors.lastname: Bessa
authors.forename: D
authors.initials: D
authors.lastname: Ferreira
authors.forename: I
authors.initials: I
authors.lastname: Melo
authors.forename: F
authors.initials: F
authors.lastname: Marques
authors.forename: J J
authors.initials: JJ
authors.lastname: Cerqueira
authors.forename: J A
authors.initials: JA
authors.lastname: Palha
authors.forename: O F X
authors.initials: OF
authors.lastname: Almeida
authors.forename: N
authors.initials: N
authors.lastname: Sousa
mesh_terms: D000339:Affect / Q000187:drug effects* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D065092:Antidiuretic Hormone Receptor Antagonists; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D054697:Cytostatic Agents / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004338:Drug Combinations; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007099:Imipramine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology
chemical_list: C456029:1-(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; D000928:Antidepressive Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D054697:Cytostatic Agents; D004338:Drug Combinations; D007211:Indoles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D005473:Fluoxetine; D008746:Methylazoxymethanol Acetate; C030667:methylazoxymethanol; D007099:Imipramine