Proneurogenic Effects of Trazodone in Murine and Human Neural Progenitor Cells

Several antidepressants increase adult hippocampal neurogenesis (ahNG) in rodents, primates, and, potentially, humans. This effect may at least partially account for their therapeutic activity. The availability of antidepressants whose mechanism of action involves different neurotransmitter receptors represents an opportunity for increasing our knowledge on their distinctive peculiarities and for dissecting the contribution of receptor subtypes in ahNG modulation. The aim of this study was to evaluate, in vitro, the effects of the antidepressant trazodone (TZD) on ahNG by using primary cultures of murine adult hippocampal neural progenitor cells (ahNPCs) and human induced pluripotent stem cell (iPSC)-derived NPCs. We demonstrated that TZD enhances neuronal differentiation of murine as well as human NPCs. TZD is a multimodal antidepressant, which binds with high affinity to 5-HT_2a, α₁, and 5-HT_1a and with lower affinity to 5-HT_2c, α₂ and 5-HTT. We demonstrated that TZD proneurogenic effects were mediated by 5-HT_2a antagonism both in murine and in human NPCs and by 5-HT_2c antagonism in murine cells. Moreover NF-κ p50 nuclear translocation appeared to be required for TZD-mediated proneurogenic effects. Interestingly, TZD had no proneurogenic effects in 5-HT depleted ahNPCs. The TDZ bell-shaped dose-response curve suggested additional effects. However, in our model 5-HT_1a and α₁/α₂ receptors had no role in neurogenesis. Overall, our data also demonstrated that serotoninergic neurotransmission may exert both positive and negative effects on neuronal differentiation of ahNPCs in vitro.