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

Abstract

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 ϫ 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.

Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder

“…Similar to what was observed with FGF2, Fgfr1 gene expression was increased in the DMS of mice after 5 weeks of voluntary ethanol consumption using an intermittent access 2 bottlechoice protocol [44]. Treatment with the FGFR1 inhibitor, PD173074 (which also inhibits FGFR3 and FGFR4), via systemic injection in mice or by direct infusion into the DMS of rats decreased ethanol consumption and preference in the intermittent access 2-bottle choice test (Table 1) [44]. PD173074 is not currently clinically approved, but second-generation pan-FGFR antagonists such as AZD4547, BGJ398, LY2874455, and JNJ-42756493 (erdafitinib) that are selective for FGFR over other tyrosine kinases are currently in clinical trials for cancer treatment [119,120].…”

“…Evidence that FGFR1 might be involved in AUD was demonstrated by Even-Chen and Barak, who found that 7 days of 2.5 g/kg ethanol injections in mice increased Fgfr1 gene expression in the DS and dorsal hippocampus 24 h after the final injection. Similar to what was observed with FGF2, Fgfr1 gene expression was increased in the DMS of mice after 5 weeks of voluntary ethanol consumption using an intermittent access 2 bottlechoice protocol [44]. Treatment with the FGFR1 inhibitor, PD173074 (which also inhibits FGFR3 and FGFR4), via systemic injection in mice or by direct infusion into the DMS of rats decreased ethanol consumption and preference in the intermittent access 2-bottle choice test (Table 1) [44].…”

“…Systemic injection of FGF2 into mice or infusion of FGF2 into the DMS of rats increased ethanol intake and preference, whereas infusion of an FGF2 neutralizing antibody (Table 1) into the rat DMS decreased ethanol drinking [42]. The regulation of FGF2 on ethanol consumption and preference relies on the downstream activation of the PI3K/AKT pathway as pre-infusion of PI3K inhibitor, wortmannin, into the DMS of rats prior to FGF2 blocked the ability of FGF2 to increase drinking [44]. The MAPK/ERK inhibitor, U0126, did not block ability of FGF2 to increase drinking, indicating that activating the PI3K pathway and not the MAPK pathway promotes drinking downstream of FGFR activation [44].…”

“…The regulation of FGF2 on ethanol consumption and preference relies on the downstream activation of the PI3K/AKT pathway as pre-infusion of PI3K inhibitor, wortmannin, into the DMS of rats prior to FGF2 blocked the ability of FGF2 to increase drinking [44]. The MAPK/ERK inhibitor, U0126, did not block ability of FGF2 to increase drinking, indicating that activating the PI3K pathway and not the MAPK pathway promotes drinking downstream of FGFR activation [44]. The effect of FGF2 on drinking is specific to ethanol, because systemic FGF2 injections into mice did not alter drinking of sucrose or saccharin solutions [42].…”

Ethanol-induced CYP2E1 Expression is Reduced by Lauric Acid via PI3K Pathway in HepG2 Cells

“…2011 ). Interestingly, recent works also showed that the need for alcohol consumption could be reduced by inhibiting fibroblast growth factor 2 (FGF2) expression via PI3K signalling ( Even-Chen & Barak 2019 ). Early works have demonstrated that activation of PI3K pathway happens via phosphorylation of tyrosine residues in the SH2 domain of p85 ( Yu et al .…”