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. 2017 Sep 6;37(36):8742-8754.
doi: 10.1523/JNEUROSCI.0890-17.2017. Epub 2017 Aug 8.

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

Oren Even-Chen  1 , Yossi Sadot-Sogrin  2 , Ohad Shaham  1 , Segev Barak  3   2
Affiliations

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

Oren Even-Chen et al. J Neurosci. .

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 Fgf2 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 Fgf2 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 Fgf2 in the DMS, and that striatal FGF2 promotes alcohol consumption, suggesting that FGF2 in the DMS is a positive regulator of alcohol drinking.SIGNIFICANCE STATEMENT 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 Fgf2 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.

Keywords: addiction; alcohol; dopamine; dorsomedial striatum; fibroblast growth factor 2.

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Figures

Figure 1.
Figure 1.
Alcohol exposure alters Fgf2 expression in the dorsal striatum (D.striatum), nucleus accumbens (NAc), and dorsal hippocampus (D.hippocampus). A, Alcohol (2.5 g/kg, 20%, i.p.) or saline was administered once, 2 h (Alcohol 2 h), 6 h (Alcohol 6 h), or 24 h (Alcohol 24 h) before brain tissue collection. n = 5–8 per group. B, Alcohol (2.5 g/kg, 20%, i.p.) or saline was administered once a day for 7 d. Brain tissues were collected 2 h (Alcohol 2 h) or 24 h (Alcohol 24 h) after the last alcohol injection. n = 5–10 per group. A, B, Fgf2 mRNA levels were determined by qRT-PCR and normalized to Gapdh, which was not affected by alcohol on its own (Fig. 1-1. Bar graphs indicate mean + SEM. Each brain region was normalized to its saline control. C, Schematic representation of the sampling regions. *p < 0.05 compared with saline control. **p < 0.01 compared with saline control.
Figure 2.
Figure 2.
Alcohol-induced increase in Fgf2 expression in the dorsal striatum is mediated by dopamine D2-like receptors. Mice were pretreated with the dopamine D2-like receptor antagonist haloperidol (1 mg/kg, i.p.) or vehicle, and 1 h later were treated with alcohol (2.5 g/kg, 20%, i.p.) or saline, once a day for 7 d. The dorsal striatum was collected 2 h after the last alcohol injection. Fgf2 mRNA levels were determined by qRT-PCR and normalized to Gapdh, which was not affected by alcohol on its own (Fig. 1-1. Bar graphs indicate mean + SEM, normalized to the saline + vehicle control group. n = 5–7 per group. *p < 0.05.
Figure 3.
Figure 3.
Voluntary alcohol consumption increases Fgf2 expression in the dorsal striatum (D.striatum). A, Experimental timeline scheme. Mice consumed alcohol in the intermittent access to 20% alcohol in 2-bottle choice paradigm for 5 weeks. Control mice consumed water only. Tissues were collected immediately at the end of the last 24-h drinking session (Alcohol group) or 24 h after the termination of the last drinking session (Withdrawal group). B, Fgf2 mRNA levels were determined by qRT-PCR, and normalized to Gapdh, which was not affected by alcohol on its own (Fig. 1-1. Bar graphs indicate mean + SEM. Each brain region was normalized to its water control. n = 8 or 9 per group. **p < 0.01 compared with water control.
Figure 4.
Figure 4.
Systemic FGF2 administration increases alcohol, but not saccharin, sucrose, or water intake. Mice were trained to consume excessive amounts of 20% alcohol (A–F), saccharin (G, H), or sucrose (I, J) solution in the intermittent access 2-bottle choice paradigm. A, B, Recombinant FGF2 (40 μg/kg, s.c.) or vehicle was injected 1 h before the beginning of the 24 h alcohol-drinking test session. A, Amount of alcohol (g/kg) consumed. B, Preference for alcohol, calculated as the ratio of the volume of alcohol solution intake/volume of total fluid intake. C–J, Recombinant FGF2 (80 μg/kg; μg/kg, s.c.) or vehicle was injected 1 h before the beginning of the 24 h alcohol (C–F), saccharin (G, H), or sucrose (I, J) drinking test session. C, Amount of alcohol (g/kg) consumed. D, Preference to alcohol. E, Water intake (ml/kg). F, Total fluid intake (alcohol + water; ml/kg). G, Saccharin (0.005% or 0.03%) solution intake (ml/kg). H, Preference for saccharin solution. I, Sucrose (0.2% or 1%) solution intake (ml/kg). J, Preference for sucrose solution. Bar graphs indicate mean + SEM. n = 7–11 per group. *p < 0.05; #p = 0.09.
Figure 5.
Figure 5.
FGF2 infusion into the dorsal striatum leads to increased alcohol consumption and preference. Rats were trained to consume alcohol in the intermittent access to 20% alcohol in 2-bottle choice paradigm for 7 weeks before cannulation. Recombinant FGF2 (200 ng/0.75 μl per hemisphere) or vehicle was infused into the dorsal striatum, 10 min before the beginning of an alcohol-drinking session. Alcohol and water intake was measured after 30 min, 4 h, and 24 h. A, Amount of alcohol (g/kg) consumed. B, Preference for alcohol, calculated as the ratio of the volume of alcohol solution intake/volume of total fluid intake. C, Water intake (ml/kg). D, Total fluid intake (alcohol + water; ml/kg). E, Schematic representation of the cannula tip placement in coronal sections (bregma + mm). Bar graphs indicate mean + SEM adjusted for a within-subjects design (Cousineau, 2005). n = 14 per group. *p < 0.05; **p < 0.01.
Figure 6.
Figure 6.
Voluntary alcohol consumption increases Fgf2 expression in the DMS of mice and rats. A, Experimental timeline scheme. Mice and rats consumed alcohol in the intermittent access to 20% alcohol in 2-bottle choice paradigm. Control animals consumed water only. Tissues were collected 24 h after the termination of the last drinking session (Withdrawal group). B, C, Fgf2 mRNA levels were determined by qRT-PCR in the DMS and DLS of mice (B) and rats (C), and normalized to Gapdh. Bar graphs indicate mean + SEM. Each brain region was normalized to its water control. D, Schematic representation of the sampling regions. n = 5 or 6 per group. *p < 0.05 compared with water control.
Figure 7.
Figure 7.
FGF2 infusion into the DMS increases alcohol consumption and preference. Rats were trained to consume alcohol in the intermittent access to 20% alcohol in 2-bottle choice paradigm for 7 weeks before cannulation. Recombinant FGF2 (200 ng/0.75 μl per hemisphere) or vehicle was infused into the DMS 10 min before the beginning of an alcohol-drinking session. Alcohol and water intake was measured at the end of the 24-h drinking session. A, Amount of alcohol (g/kg) consumed. B, Preference for alcohol, calculated as the ratio of the volume of alcohol solution intake/volume of total fluid intake. C, Water intake (ml/kg). D, Total fluid intake (alcohol + water; ml/kg). E, Schematic representation of the cannula tip placement in coronal sections (bregma + mm). Bar graphs indicate mean + SEM adjusted for a within-subjects design (Cousineau, 2005). n = 8 per group. *p < 0.05; **p < 0.01.
Figure 8.
Figure 8.
Inhibition of FGF2 activity in the DMS decreases alcohol consumption and preference. Rats were trained to consume alcohol in the intermittent access to 20% alcohol in 2-bottle choice paradigm for 7 weeks before cannulation. Neutralizing antibody against FGF2 (750 ng/0.75 μl per hemisphere) or control IgG was infused into the DMS 1 h before the beginning of an alcohol-drinking session. Alcohol and water intake was measured at the end of the 24-h drinking session. A, Amount of alcohol (g/kg) consumed. B, Preference for alcohol, calculated as the ratio of the volume of alcohol solution intake/volume of total fluid intake. C, Water intake (ml/kg). D, Total fluid intake (alcohol + water; ml/kg). E, Schematic representation of the cannula tip placement in coronal sections (bregma + mm). Bar graphs indicate mean + SEM adjusted for a within-subjects design (Cousineau, 2005). n = 15 per group. *p < 0.05; **p < 0.01.
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