FGF2 is an endogenous regulator of alcohol reward and consumption

Even-Chen, Oren; Herburg, Leonie; Kefalakes, Ekaterini; Urshansky, Nataly; Grothe, Claudia; Barak, Segev

doi:10.1111/adb.13115

Cited by 10 publications

(7 citation statements)

References 65 publications

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“…We observed that male C57BL/6J mice that were offered intermittent access to 20% ethanol and water voluntarily consumed stable amounts of ethanol with an average of 9g/kg/24 h ( Supplemental Figure S1a ). These results are consistent with other studies showing that male C57BL/6J mice consumed similar levels (10 g/kg/24 h) when offered 20% of alcohol [ 33 ]. Furthermore, mice lacking FGF-2 consumed significantly lower amounts of ethanol compared with wild-type mice [ 33 ].…”

Section: Discussionsupporting

confidence: 93%

“…These results are consistent with other studies showing that male C57BL/6J mice consumed similar levels (10 g/kg/24 h) when offered 20% of alcohol [ 33 ]. Furthermore, mice lacking FGF-2 consumed significantly lower amounts of ethanol compared with wild-type mice [ 33 ]. Altogether, this leads to the assumption that multiple cycles of heavy drinking bouts and withdrawal periods lead to neuroadaptations in certain brain areas that induce ethanol dependence and addiction [ 35 , 36 ].…”

Section: Discussionsupporting

confidence: 93%

“…First, we examined the drinking behavior of male mice that were trained to consume 20% ( v / v ) alcohol in intermittent access to 20% alcohol in a two-bottle choice (IA2BC) drinking procedure [ 32 , 33 ] ( Supplemental Figure S1a ). During six weeks of intermittent access to 20% alcohol, mice exhibited stable consumption levels with an average of 9 g/kg/24 h ( Supplemental Figure S1b ).…”

Section: Resultsmentioning

confidence: 99%

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Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1

Herburg

Rhein

Kubinski

et al. 2023

IJMS

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Alcohol abuse accounts for 3.3 million deaths annually, rendering it a global health issue. Recently, fibroblast growth factor 2 (FGF-2) and its target, fibroblast growth factor receptor 1 (FGFR1), were discovered to positively regulate alcohol-drinking behaviors in mice. We tested whether alcohol intake and withdrawal alter DNA methylation of Fgf-2 and Fgfr1 and if there is a correlation regarding mRNA expression of these genes. Blood and brain tissues of mice receiving alcohol intermittently over a six-week period were analyzed using direct bisulfite sequencing and qRT-PCR analysis. Assessment of Fgf-2 and Fgfr1 promoter methylation revealed changes in the methylation of cytosines in the alcohol group compared with the control group. Moreover, we showed that the altered cytosines coincided with binding motives of several transcription factors. We also found that Fgf-2 and Fgfr1 gene expression was significantly decreased in alcohol-receiving mice compared with control littermates, and that this effect was specifically detected in the dorsomedial striatum, a brain region involved in the circuitry of the reward system. Overall, our data showed alcohol-induced alterations in both mRNA expression and methylation pattern of Fgf-2 and Fgfr1. Furthermore, these alterations showed a reward system regional specificity, therefore, resembling potential targets for future pharmacological interventions.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1

Herburg

Rhein

Kubinski

et al. 2023

IJMS

View full text Add to dashboard Cite

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“…Systemic administration of recombinant FGF-2 (rFGF-2) increased alcohol consumption in mice, whereas inhibition of endogenous FGF-2 reduced alcohol intake (Even-Chen et al, 2017). Recently, it was also shown that mice lacking endogenous FGF-2 consumed lower amounts of alcohol, an alcohol-specific effect, as the intake and preference of sucrose, a natural reward, was unaffected (Even-Chen et al, 2022). These results support our present finding that FGF-2 KO mice consume less alcohol compared with wild types, manifesting FGF-2 as an important regulator of alcohol drinking behaviour in mice.…”

Section: Discussionmentioning

confidence: 99%

A dual‐omics approach on the effects of fibroblast growth factor‐2 (FGF‐2) on ventral tegmental area dopaminergic neurons in response to alcohol consumption in mice

Hose,

Langenhagen,

Kefalakes

et al. 2024

Eur J of Neuroscience

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Harmful alcohol consumption is a major socioeconomic burden to the health system, as it can be the cause of mortality of heavy alcohol drinkers. The dopaminergic (DAergic) system is thought to play an important role in the pathogenesis of alcohol drinking behaviour; however, its exact role remains elusive. Fibroblast growth factor 2 (FGF‐2), a neurotrophic factor, associated with both the DAergic system and alcohol consumption, may play an important role in DAergic neuroadaptations during alcohol abuse. Within this study, we aimed to clarify the role of endogenous FGF‐2 on the DAergic system and whether there is a possible link to alcohol consumption. We found that lack of FGF‐2 reduces the alcohol intake of mice. Transcriptome analysis of DAergic neurons revealed that FGF‐2 knockout (FGF‐2 KO) shifts the molecular fingerprint of midbrain dopaminergic (mDA) neurons to DA subtypes of the ventral tegmental area (VTA). In line with this, proteomic changes predominantly appear also in the VTA. Interestingly, these changes led to an altered regulation of the FGF‐2 signalling cascades and DAergic pathways in a region‐specific manner, which was only marginally affected by voluntary alcohol consumption. Thus, lack of FGF‐2 not only affects the gene expression but also the proteome of specific brain regions of mDA neurons. Our study provides new insights into the neuroadaptations of the DAergic system during alcohol abuse and, therefore, comprises novel targets for future pharmacological interventions.

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“…Sensitivity to EtOH reflects the threshold to become sedated in response to the inhibition of CNS activity (Chen et al, 2021; Childs et al, 2019; Ozburn et al, 2013). Individual sensitivity to EtOH is determined by the interaction between the pharmacological effect of EtOH and individual responses to EtOH (Even‐Chen et al, 2017, 2022; Ye et al, 2021). Our study was designed to clarify the mechanism underlying sensitivity to the sedative‐hypnotic effect of EtOH in mice.…”

Section: Discussionmentioning

confidence: 99%

G protein‐coupled receptor 158 modulates sensitivity to the sedative‐hypnotic effect of ethanol in male mice

Wei

Zheng

Chang

et al. 2023

Alcohol: Clinical and Experimental Research

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Background Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein‐coupled receptor 158 (GPR158) in modulating sensitivity to the sedative‐hypnotic effect of ethanol has not been investigated. Methods Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158−/− mice and wild‐type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open‐field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158−/− mice (n = 6/genotype). We also tested CamK2A‐Cre;Gpr158fl/fl (n = 9) and Vgat‐Cre;Gpr158fl/fl mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). Results Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = −5.241, p = 0.0001, without altering spontaneous activity, t(14) = −0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin‐dependent protein kinase II alpha‐positive (CamK2A+) neurons, t(16) = −2.914, p = 0.01, and by 92% in the vesicular GABA transporter‐positive (Vgat+) neurons, t(9.802) = −2.519, p = 0.023. Locomotion was not altered in Camk2A‐Cre;Gpr158fl/fl, t(16) = 0.49, p = 0.631 or Vgat‐Cre;Gpr158fl/fl mice, t(16) = 0.035, p = 0.972. Conclusions This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative‐hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.

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FGF2 is an endogenous regulator of alcohol reward and consumption

Cited by 10 publications

References 65 publications

Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1

Chronic Voluntary Alcohol Consumption Alters Promoter Methylation and Expression of Fgf-2 and Fgfr1

A dual‐omics approach on the effects of fibroblast growth factor‐2 (FGF‐2) on ventral tegmental area dopaminergic neurons in response to alcohol consumption in mice

G protein‐coupled receptor 158 modulates sensitivity to the sedative‐hypnotic effect of ethanol in male mice

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