¹Institute of Experimental Endocrinology, Department of Neuroscience, Bratislava, Slovakia, ²Institute of Molecular Physiology and Genetics SAS, Cell Physiology and Genetics, Bratislava, Slovakia

Background: Fibroblast growth factor 2 (FGF2) displays diverse neuroactive properties. It has been shown to induce anxiolytic and antidepressant-like effects in rodents, yet it can also increase alcohol consumption, while the FGFR1 antagonist PD173074 reduces it, suggesting potential pro-addictive actions of FGF2 (Paliokha et al., Int J Neuropsychopharmacol 28:i200, 2025). Our previous work revealed that FGF-2 exerts heterogeneous effects on monoaminergic neurons, including modulation of neuronal activity in the VTA and LC, and inhibition of burst firing in serotonergic neurons of the dorsal raphe nucleus (DRN). Importantly, this inhibitory effect was not prevented by PD173074, indicating that FGFR1 is unlikely to mediate the response (Grinchii et al., DrugAlcohol Depend 248:109920, 2023). Given the essential roles of serotonergic and dopaminergic systems in mood regulation and addiction, FGF-2–induced changes in 5-HT and/or dopaminergic neuronal activity may underlie its reported behavioral effects.

Aims & Objectives: The aim of our study was to determine which receptor mediates the effects of FGF-2 in the DRN using selective receptor antagonists.

Method: Adult male Wistar rats (n=10) were randomly assigned to two groups: the experimental group, which received intracerebroventricular administration of the selective FGFR2 antagonist RLY-4008, and the control group, which received equivalent volume of vehicle (10% DMSO, 45% PEG, 5% Tween-80, 40% water). Animals were anesthetized with chloral hydrate (0.4 g/kg, i.p.) and secured in a stereotaxic frame. After midline scalp incision, a burr hole was drilled above the lateral ventricle, and a Hamilton microsyringe was lowered according to stereotaxic coordinates. A total of 5 μL of RLY-4008 or vehicle was delivered in 50-nL increments, each followed by a 1-minute pause to prevent reflux and osmotic shock; the syringe remained in place for several minutes after the final injection. One hour later, a second burr hole was made above the dorsal raphe nucleus (DRN), and extracellular single-unit recordings were obtained using a glass microelectrode filled with 2 M NaCl. Serotonergic neurons were identified by their slow, regular firing pattern and broad action potential waveform. Firing rate and burst parameters were quantified offline, and statistical analyses were performed using Statistica (StatSoft).

Results: In our experiment, intracerebroventricular administration of the selective FGFR2 antagonist RLY-4008 did not produce any significant changes in the spontaneous firing rate or burst parameters of DRN serotonergic neurons compared with the vehicle-treated control group.

Discussion & Conclusions: 

Based on our current results and previous findings, we conclude that FGF-2 modulates burst activity of serotonergic neurons in the dorsal raphe nucleus (DRN). Whereas recombinant FGF-2 strongly inhibited burst firing in these neurons, neither FGFR1 blockade with PD173074 nor selective FGFR2 inhibition with RLY-4008 produced significant effects on their electrophysiological activity. Published evidence indicates that FGFR3 expression in the central nervous system is minimal and functionally insignificant, making it an unlikely mediator of FGF-2 action. These observations suggest that the modulatory influence of FGF-2 on DRN 5-HT neurons may instead be mediated through FGFR4, which is more widely expressed in the CNS. Further studies are needed to confirm the involvement of FGFR4 and clarify the receptor mechanisms through which FGF-2 regulates serotonergic neuronal excitability.