FIBROBLAST GROWTH FACTOR 2 MODULATES CENTRAL MONOAMINERGIC NEURONS IN VIVO
Authors: Paliokha *Ruslan , Grinchii Daniil , Dekhtiarenko Roman , Segev Barak , Dremencov Eliyahu 
Published: February 2025

Background

Fibroblast growth factor 2 (FGF2) was reported to induce anxiolytic and antidepressant- like effect in rodents[1]. On the other hand, FGF2 stimulates[2], and an antagonist of the FGF2 receptor 1 (FGFR1) PD173074 decreases alcohol consumption in rodents[3], suggesting that FGF2 might have a pro-addictive effect. Since the central serotonergic (5-HT) and dopaminergic systems are fundamental in the mood and addiction, putative antidepressant, and pro-addictive effects of FGF2 might be mediated via mechanisms involving 5-HT and/or dopaminergic neuronal firing activity.

Aims & Objectives

We aimed to examine the effects recombinant FGF2 and PD173074on the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN) and dopaminergic neurons of the ventral tegmental area (VTA).

Methods

Adult male and female Wistar rats were used in experiments. In the first experiment, rats were randomly divided into two groups. The first group received subcutaneous (s.c.) injection of FGF2 (80 &micro;g/kg); the second group received vehicle. One hour after FGF2 or vehicle injecting, rats will be anesthetized with chloral hydrate (0.4 g/kg, intraperitoneally: i.p.) and fixed in a stereotaxic frame. The electrode was lowered via the DRN or VTA. Dopaminergic and 5-HT neurons were identified identified according to their excitability pattern and the waveform of the action potentials[4] and recorded. In the second experiment, the rats were divided into two groups again, and received no pre-treatment. In the first group, the electrode was inserted to the DRN, in the second-to the VTA. After a spontaneously active 5-HT or dopaminergic neuron was recognized and its basal activity recorded, PD173074 was intravenously (i.v.) injected (via catheter placed in the femoral vein), in cumulative doses of 6,9,12 and 15 mg/kg. The neuronal firing rate after the administration of each dose of PD173074 was compared to the basal firing activity of the same neuron.

Results

FGF2 stimulated dopaminergic neurons of the VTA in both sexes. PD173074, vice versa, inhibited dopaminergic neurons in a dose-dependent way. The mean spontaneous firing rate of 5-HT neurons was higher in males comparing to females. It was not, however, significantly different between FGF2 and vehicle-treated rats. FGF2, however, supressed the burst mode of firing of 5-HT neurons in males, but not in females. According to our preliminary results, PD173074 had no effect on the excitability of 5-HT neurons.

Discussion & Conclusion

Our results indicate that FGF2 enhance dopaminergic neuronal firing activity, via a mechanism involving FGFR1. The observed sex differences in the firing rate of 5-HT neurons is consistent with our previous findings[5]. Since the burst firing of 5-HT neurons has an enhancing effect on nerve terminal 5-HT release[6], suppression of this mode of firing activity by FGF2 might attenuate central 5-HT transmission. It is possible that FGF2 modulates mood and alcohol consumption via regulation of 5-HT and dopamine transmission. This work was supported by the Slovak Research and Development Agency (grants APVV-19-0435 and APVV-20-0202) and Scientific Grant Agency of Ministry of Education of Slovak Republic and Slovak Academy of Sciences (grants VEGA-2/0057/22 and VEGA-2/0045/24).

References

1.Elsayed, M.; Banasr, M.; Duric, V.; Fournier, N. M.; Licznerski, P.; Duman, R. S., Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression. Biol Psychiatry 2012, 72, (4), 258-65.

2.Even-Chen, O.; Sadot-Sogrin, Y.; Shaham, O.; Barak, S., Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption. J Neurosci 2017, 37, (36), 8742-8754.

3.Even-Chen, O.; Barak, S., Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum. J Neurosci 2019, 39, (40), 7947-7957.

4.Grinchii, D.; Lacinová, Ľ.; Dremencov, E., Effects of delta-opioid receptor ligands on the excitability of rat hippocampal glutamate and brainstem monoamine neurons in vivo. Gen Physiol Biophys 2023.

5.Dremencov, E.; Dekhtiarenko, R.; Grinchii, D.; Vinas-Noguera, M.; Csatló sová, K.; Dubovický, M.; Lacinová, Ľ., Sex-specific effect of perinatal mirtazapine administration and pregestational stress on the excitability of serotonergic neurons in rats. In Abstracts of the 33rd CINP Hybrid World Congress of Neuropsychopharmacology, Taipei, Taiwan, 2022; p 109.

6.Gartside, S. E.; Hajó s-Korcsok, E.; Bagdy, E.; Há rsing, L. G., Jr.; Sharp, T.; Hajó s, M., Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons. Neuroscience 2000, 98, (2), 295-300.