Fibroblast Growth Factor 2 in the Dorsomedial Striatum Is a Novel Positive Regulator of Alcohol Consumption

Abstract

Repeated alcohol intake leads to mesostriatal neuroadaptations, resulting in drinking escalation and addiction phenotypes. Fibroblast growth factor 2 (FGF2) has been shown to interact with the mesostriatal dopaminergic system, and has been implicated in the actions of psychostimulants in the brain, and in several psychiatric disorders. Here, we report on a positive regulatory feedback loop of alcohol and FGF2 in rodent models. Specifically, we found that acute alcohol exposure (2.5 g/kg, i.p.) increased the mRNA expression of in the dorsal hippocampus, nucleus accumbens, and dorsal striatum. Longer alcohol exposure (7 d × 2.5 g/kg, i.p.) restricted these increases to the dorsal striatum, and the latter effect was blocked by the dopamine D2-like receptor antagonist haloperidol. Voluntary prolonged and excessive alcohol consumption in a 2-bottle choice procedure increased expression selectively in dorsomedial striatum (DMS) of both mice and rats. Importantly, we found that systemic administration of recombinant FGF2 (rFGF2) in mice, or rFGF2 infusion into the dorsal striatum or DMS of rats, increased alcohol consumption and preference, with no similar effects on saccharin or sucrose consumption. Finally, we found that inhibition of the endogenous FGF2 function in the DMS, by an anti-FGF2 neutralizing antibody, suppressed alcohol consumption and preference. Together, our results suggest that alcohol consumption increases the expression of in the DMS, and that striatal FGF2 promotes alcohol consumption, suggesting that FGF2 in the DMS is a positive regulator of alcohol drinking. Long-term alcohol intake may lead to neuroadaptations in the mesostriatal reward system, resulting in addiction phenotypes. Fibroblast growth factor 2 (FGF2) is crucial for the development and maintenance of the mesostriatal dopaminergic system. Here, we provide evidence for the involvement of FGF2 in alcohol-drinking behaviors. We show that alcohol increases expression in the dorsal striatum, an effect mediated via dopamine D2-like receptors. Importantly, we show that infusion of recombinant FGF2 into the dorsomedial striatum increases alcohol consumption, whereas inhibiting the endogenous FGF2 function suppresses consumption. Thus, FGF2 is an alcohol-responsive gene constituting a positive regulatory feedback loop with alcohol. This loop leads to facilitation of alcohol consumption, marking FGF2 as a potential new therapeutic target for alcohol addiction.

The role of fibroblast growth factor 2 in drug addiction

“…In addition to alcohol affecting Fgf2 expression, FGF2 was shown to mediate alcohol consumption. Specifically, systemic administration of recombinant FGF2 (80 lg/kg) to mice increased alcohol consumption and preference without affecting the consumption of water or natural rewards (sweetened solution: sucrose or saccharin) (Even-Chen et al, 2017). Moreover, infusion of recombinant FGF2 (200 ng/hemisphere) into the dorsal striatum or the DMS of rats increased alcohol consumption and preference.…”

“…Acute alcohol injection (2.5 g/kg) increased Fgf2 mRNA levels in the mouse dorsal striatum, NAc, and hippocampus (Even‐Chen et al ., ). However, longer alcohol exposure (2.5 g/kg injection once a day for 7 days) limited these changes to the dorsal striatum at both its sub‐regions: the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS), and these increases were found to be mediated by DA D2‐like receptor activation (Even‐Chen et al ., ).…”

“…Moreover, infusion of recombinant FGF2 (200 ng/hemisphere) into the dorsal striatum or the DMS of rats increased alcohol consumption and preference. In contrast, blocking FGF2 activity with an anti‐FGF2 neutralizing antibody suppressed alcohol intake and preference (Even‐Chen et al ., ). Thus, FGF2 acts as a positive regulator of alcohol consumption.…”

“…Voluntary consumption of high levels of alcohol for 5-7 weeks via the intermittent access to 20% alcohol in two-bottle choice (IA2BC) procedure (Carnicella et al, 2014) increased Fgf2 levels in the DMS, but not the DLS, of both mice and rats (Even-Chen et al, 2017). Thus, while short exposure to alcohol leads to widespread increases in the brain Fgf2 expression, as the exposure to alcohol extends and becomes more robust the effects on Fgf2 expression become more spatially specific.…”

bFGF expression is differentially regulated by cocaine seeking versus extinction in learning-related brain regions

“…Functionally, systemic bFGF administration can facilitate later acquisition of cocaine selfadministration (Turner et al 2009), and bFGF in VTA is necessary for amphetamine-induced increases in locomotion and sensitization . Moreover, neutralizing bFGF in IL-mPFC can facilitate extinction following cocaine self-administration (Hafenbreidel et al 2015), and neutralizing bFGF in the dorsal striatum can reduce alcohol seeking and reinstatement (Even-Chen et al 2017). However, intra-BLA bFGF infusions can facilitate extinction of conditioned fear (Graham and Richardson 2011a,b).…”