Abstract: 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 ?-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 ?-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 ?-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.

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