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A role for nuclear β-catenin in SNRI antidepressant-induced hippocampal cell proliferation

AutorMostany, Ricardo; Valdizán, Elsa M. ; Pazos, Ángel
Fecha de publicación2008
EditorElsevier
CitaciónNeuropharmacology 55(1): 18-26 (2008)
ResumenIncreasing evidences have been accumulated during recent years suggesting a role for antidepressant drugs (ADs) as hippocampal neurogenesis enhancers, but the information about the transductional mechanisms involved in this response is very limited. We have studied in the adult rat hippocampus the effects of chronic treatment with the dual reuptake inhibitor (SNRI) venlafaxine on both cellular proliferation rate and expression of key effectors of several signaling pathways. Increased cell proliferation (BrdU incorporation) in subgranular zone (SGZ) was achieved after chronic treatment with a high dose (40 mg/kg/day) of venlafaxine. However, significant increases in the immunoreactivity of hippocampal β-catenin in SGZ were already detected after administration of a lower dose of the drug (10 mg/kg/day). Western blot and immunoelectron microscopy studies demonstrated an increased presence of β-catenin at the nuclear level. An increase in cytosolic AKT levels was also observed in venlafaxine-treated animals. These results suggest that the hippocampal proliferative effect of chronic venlafaxine, only evident when both serotonin (5-HT) and noradrenaline/norepinephrine (NE) reuptake systems are inhibited, requires a strong activation of intracellular signaling through Wnt (β-catenin translocation) and AKT/PKB pathways. This activation would probably result in an increase of the expression of cell cycle regulator genes. Furthermore pERK2/ERK2 rate was also increased in the hippocampus of AD-treated animals, while no differences in the levels of CREB and p-CREB were observed. These results illustrate the complexity of the intracellular events underlying the neurogenetic responses of ADs. They also support the relevance of such effects for the therapeutic effects of these drugs. © 2008 Elsevier Ltd. All rights reserved.
URIhttp://hdl.handle.net/10261/50132
DOI10.1016/j.neuropharm.2008.04.012
Identificadoresdoi: 10.1016/j.neuropharm.2008.04.012
issn: 0028-3908
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