Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects

El pdf del artículo es la versión pre-print.[Background and Purpose]: 5-HT2A 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-HT1A 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-HT1A 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-HT2A 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-HT1A receptor desensitization in the dorsal raphe nucleus.This work has been supported by Instituto de Salud Carlos III (Red Investigación de Enfermedades Mentales, REMTAP), Ministerio de Ciencia e Innovación SAF07-61862 and Fundación Alicia Koplowitz.Peer reviewe