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Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain‐derived neurotrophic factor, β‐catenin and antidepressant‐like effects
Author(s) -
PilarCuéllar F,
Vidal R,
Pazos A
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01516.x
Subject(s) - ketanserin , fluoxetine , tropomyosin receptor kinase b , antidepressant , medicine , endocrinology , hippocampal formation , neurotrophic factors , brain derived neurotrophic factor , behavioural despair test , dentate gyrus , pharmacology , tricyclic antidepressant , serotonin reuptake inhibitor , hippocampus , serotonin , chemistry , receptor , 5 ht receptor
BACKGROUND AND PURPOSE 5‐HT 2A receptor antagonists improve antidepressant responses when added to 5‐HT‐selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5‐hydroxytryptaminergic system in the antidepressant‐like effect of this combined treatment, given subchronically. EXPERIMENTAL APPROACH Expression of brain‐derived neurotrophic factor (BDNF) and its receptor (TrkB), 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation, and β‐catenin protein expression in different cellular fractions, as well as 5‐HT 1A receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. KEY RESULTS mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of β‐catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5‐HT 1A receptor function in any of the groups studied. CONCLUSIONS AND IMPLICATIONS The antidepressant‐like effect induced by subchronic co‐treatment with a SSRI and a 5‐HT 2A receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane‐associated β‐catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5‐HT 1A receptor desensitization in the dorsal raphe nucleus.