There are no clear data on the molecular mechanism by which the hippocampal 5-HT transmission contributes to the neuroprotective and antidepressant effects of 5-HT uptake blockers. Previously, we revealed that a 5-HT1A agonist may induce phosphorylation of FGFR1 and ERK1/2 in rat hippocampus independent of FGF-2, suggesting transactivation of FGFR1 tyrosine kinase in the absence of neurotrophic factor binding. As extension of previous work, using BRET analysis and coimmunoprecipitation in cellular models, FGFR1-5-HT1A heteroreceptor complexes have been demonstrated and agonist modulation characterized. In vitro assays on ERK1/2 phosphorylation in HEK cells and primary hippocampal cultures have shown synergistic increases in signaling upon coactivation with FGF-2 and 5-HT1A agonist. Coactivation of the FGFR1/5-HT1A heteroreceptor complex also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures. The findings indicate that neurotrophic effects of 5-HT in brain may in part be mediated by activation of the 5-HT1A receptor in the hippocampal FGFR1/5-HT1A heteroreceptor complex enhancing the FGFR1 signaling and playing a significant role in hippocampal plasticity.