The role of 5‐hydroxytryptamine receptor subtypes in the regulation of brain‐derived neurotrophic factor gene expression

Objectives The study aims to investigate the role of 5‐hydroxytryptamine receptor subtypes in mediating the inhibitory effect of the selective serotonin reuptake inhibitor (fluoxetine on brain‐derived neurotrophic factor gene ( bdnf ) expression in rat hippocampus. Methods In situ hybridization was used for regional determination of bdnf expression levels in hippocampal brain slices from normal, lesioned (5‐hydroxytryptamine or noradrenaline) or adrenalectomized rats; treated with fluoxetine and/or 5‐hydroxytryptamine selective ligands. Key findings Our study shows that the transient fluoxetine‐induced down‐regulation of bdnf gene expression depends on an intact 5‐hydroxytryptamine but not noradrenaline system or circulating glucocorticoids. Pretreatment with the 5‐hydroxytryptamine 4 antagonist SB ‐204070 blocked the overall fluoxetine‐induced inhibition of bdnf levels in hippocampus, while pretreatment with the 5‐hydroxytryptamine 2 antagonists ketanserin had an effect in the CA 3 but not in the dentate gyrus sub‐region of hippocampus. The 5‐hydroxytryptamine 1A antagonist WAY ‐100635 and the 5‐hydroxytryptamine 3 antagonist granisetron were both ineffective. Conclusions Our study found strong support for a primary effect of 5‐hydroxytryptamine but not noradrenaline or circulating glucocorticoids in the mediation of fluoxetine‐induced down‐regulation of bdnf expression. More specifically, we also show that 5‐hydroxytryptamine 4 receptor‐stimulation seems to play a pivotal role in this effect.