Rolle des Fibroblasten-Wachstumsfaktors-2 in Alkoholkonsumstörungen
Kognitive, systemische und Verhaltensneurobiologie
Molekulare und zelluläre Neurologie und Neuropathologie
Zusammenfassung der Projektergebnisse
Fibroblast growth factor 2 (FGF-2), an essential modulator of neuronal regulation, can be associated with drug-related behaviors, including alcohol consumption. Recent studies suggest that alcohol administration increases Fgf-2 gene expression in addiction-related brain regions, specifically in the mesolimbic and nigrostriatal DAergic systems. Furthermore, manipulations of the endogenous FGF-2 functions have been shown to modulate alcohol consumption behavior in rodents. Despite the promising results, there is an urgent need for further research identifying the molecular mechanisms involved in the bidirectional association of alcohol and FGF-2. In the project specific aspects of alcohol – FGF-2 relationship were studied. Previous studies have shown that the mRNA expression of Fgf2 and its receptor, Fgfr1 levels are increased in the striatum of rodents following long-term alcohol exposure, and that enhancing FGF-2-FGFR1 activity increases alcohol intake, whereas their inhibition suppresses alcohol consumption. Related to the present project, the role of endogenous Fgf-2 on alcohol consumption and the associated rewarding properties and hypnotic effects of alcohol we examined. We found that FGF-2 knockout (FGF-2 KO) mice showed reduced alcohol consumption and preference when tested in a two-bottle choice paradigm. Importantly, these effects were specific to alcohol, as consumption of natural rewards (sucrose) or water was unaffected by Fgf-2 depletion. Moreover, we found that Fgf-2 deficiency disrupted alcohol-conditioned place preference (CPP) without affecting fear conditioning. Finally, FGF-2 KO mice took longer to recover from the loss of righting reflex (LORR) and showed higher blood alcohol concentrations when exposed to an intoxicating dose of alcohol. We further analyzed the effects of chronic voluntary alcohol consumption on the DNA methylation of Fgf-2 and its primary target, the fibroblast growth factor receptor 1 (Fgfr1) and whether there is a correlation with the subsequent mRNA expression of those genes. Here we found that repeated cycles of alcohol consumption and withdrawal affect the promoter methylation of Fgf-2 and Fgfr1 in a brain region-specific manner. We further found alcohol-induced alterations in the mRNA expression of Fgf-2 and Fgfr1. This effect was specific to the dorsomedial striatum (DMS), a brain region involved in the circuitry of the reward system. Next, as FGF2 is a protein that is involved in the development and maintenance of the brain dopamine system, we assessed its effect on the firing of dopaminergic projections from the midbrain to the striatum. We found that increases in FGF-2 led to increased firing of dopaminergic neurons in the midbrain, which also increase operant alcohol self-administration, an animal model of addiction. The FGFR1 inhibitor PD173074 suppressed the firing of dopaminergic neurons and reduced alcohol consumption. PD173074 also reduces post-abstinence relapse to alcohol consumption, but only in male rats. These findings suggest that targeting the FGF2-FGFR1 pathway could be a potential treatment for alcohol use disorder. By combining transcriptomic and proteomic approaches, we found that loss of Fgf-2 alters the transcriptional fingerprint of midbrain DAergic neurons as well as protein translation and signaling pathways in brain regions of the DAergic system. In conclusion, the project reveals a bidirectional association between alcohol consumption and FGF-2, demonstrating the role of the growth factor in alcohol-related behavior, including consumption, preference, and rewarding effects. Additionally, we provide the first information about the potential mechanism of action, by which FGF-2 interacts with alcohol consumption, including FGF-2's impact on dopaminergic transmission, epigenetic regulation, and the transcriptional profile of dopamineproducing neurons, highlighting its potential as a therapeutic target for alcohol use disorder via modulation of the dopaminergic system.
Projektbezogene Publikationen (Auswahl)
-
FGF2 is an endogenous regulator of alcohol reward and consumption. Addiction Biology, 27(2).
Even‐Chen, Oren; Herburg, Leonie; Kefalakes, Ekaterini; Urshansky, Nataly; Grothe, Claudia & Barak, Segev
-
Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1. International Journal of Molecular Sciences, 24(4), 3336.
Herburg, Leonie; Rhein, Mathias; Kubinski, Sabrina; Kefalakes, Ekaterini; Levin, Greenwald Matar; Gielman, Simona; Barak, Segev; Frieling, Helge & Grothe, Claudia
-
FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission. Drug and Alcohol Dependence, 248, 109920.
Grinchii, Daniil; Levin-Greenwald, Matar; Lezmy, Noa; Gordon, Tamar; Paliokha, Ruslan; Khoury, Talah; Racicky, Matej; Herburg, Leonie; Grothe, Claudia; Dremencov, Eliyahu & Barak, Segev
