RGD Reference Report - Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum. - Rat Genome Database

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Inhibition of FGF Receptor-1 Suppresses Alcohol Consumption: Role of PI3 Kinase Signaling in Dorsomedial Striatum.

Authors: Even-Chen, Oren  Barak, Segev 
Citation: Even-Chen O and Barak S, J Neurosci. 2019 Oct 2;39(40):7947-7957. doi: 10.1523/JNEUROSCI.0805-19.2019. Epub 2019 Aug 2.
RGD ID: 405855874
Pubmed: PMID:31375540   (View Abstract at PubMed)
PMCID: PMC6774404   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.0805-19.2019   (Journal Full-text)

Excessive alcohol intake leads to mesostriatal neuroadaptations, and to addiction phenotypes. We recently found in rodents that alcohol increases fibroblast growth factor 2 (FGF2) expression in the dorsomedial striatum (DMS), which promotes alcohol consumption. Here, we show that systemic or intra-DMS blockade of the FGF2 receptor, FGF receptor-1 (FGFR1), suppresses alcohol consumption, and that the effects of FGF2-FGFR1 on alcohol drinking are mediated via the phosphoinositide 3 kinase (PI3K) signaling pathway. Specifically, we found that sub-chronic alcohol treatment (7 d × 2.5 g/kg, i.p.) increased Fgfr1 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased Fgfr1 expression selectively in DMS. Importantly, systemic administration of the FGFR1 inhibitor PD173074 to mice, as well as its infusion into the DMS of rats, decreased alcohol consumption and preference, with no effects on natural reward consumption. Finally, inhibition of the PI3K, but not of the mitogen-activated protein kinase (MAPK) signaling pathway, blocked the effects of FGF2 on alcohol intake and preference. Our results suggest that activation of FGFR1 by FGF2 in the DMS leads to activation of the PI3K signaling pathway, which promotes excessive alcohol consumption, and that inhibition of FGFR1 may provide a novel therapeutic target for alcohol use disorder.SIGNIFICANCE STATEMENT Long-term alcohol consumption causes neuroadaptations in the mesostriatal reward system, leading to addiction-related behaviors. We recently showed that alcohol upregulates the expression of fibroblast growth factor 2 (FGF2) in dorsomedial striatum (DMS) or rats and mice, and in turn, FGF2 increases alcohol consumption. Here, we show that long-term alcohol intake also increases the expression of the FGF2 receptor, FGFR1 in the DMS. Importantly, inhibition of FGFR1 activity by a selective receptor antagonist reduces alcohol drinking, when given systemically or directly into the DMS. We further show that the effects of FGF2-FGFR1 on alcohol drinking are mediated via activation of the PI3K intracellular signaling pathway, providing an insight on the mechanism for this effect.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FGF2Humanalcohol use disorder  ISOFgf2 (Rattus norvegicus) RGD 
Fgf2Ratalcohol use disorder  IMP  RGD 
Fgf2Mousealcohol use disorder  ISOFgf2 (Rattus norvegicus) RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Fgf2Ratresponse to wortmannin  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fgf2  (fibroblast growth factor 2)

Genes (Mus musculus)
Fgf2  (fibroblast growth factor 2)

Genes (Homo sapiens)
FGF2  (fibroblast growth factor 2)


Additional Information