School of Psychological Sciences, and.
School of Psychological Sciences, and
J Neurosci. 2019 Oct 2;39(40):7947-7957. doi: 10.1523/JNEUROSCI.0805-19.2019. Epub 2019 Aug 2.
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 mRNA expression in the dorsal hippocampus and dorsal striatum. However, prolonged and excessive voluntary alcohol consumption in a two-bottle choice procedure increased 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. 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.
过量饮酒会导致中脑边缘神经系统的神经适应性改变，并导致成瘾表型。我们最近在啮齿动物中发现，酒精会增加背内侧纹状体（DMS）中的成纤维细胞生长因子 2（FGF2）表达，从而促进酒精摄入。在这里，我们表明，系统或 DMS 内 FGF2 受体，FGFR1 的阻断抑制酒精消耗，并且 FGF2-FGFR1 对酒精饮用的影响是通过磷酸肌醇 3 激酶（PI3K）信号通路介导的。具体来说，我们发现，亚慢性酒精处理（7d×2.5g/kg，ip）增加了背侧海马体和背侧纹状体中的 mRNA 表达。然而，在双瓶选择程序中，长期和过度的自愿性酒精消耗选择性地增加了 DMS 中的 表达。重要的是，FGFR1 抑制剂 PD173074 向小鼠的全身给药，以及其向大鼠 DMS 的输注，减少了酒精消耗和偏好，而对天然奖赏消耗没有影响。最后，PI3K 的抑制，但不是丝裂原活化蛋白激酶（MAPK）信号通路的抑制，阻断了 FGF2 对酒精摄入和偏好的影响。我们的结果表明，DMS 中的 FGF2 通过 FGFR1 的激活导致 PI3K 信号通路的激活，从而促进了过度的酒精消耗，并且 FGFR1 的抑制可能为酒精使用障碍提供了一个新的治疗靶点。长期饮酒会导致中脑边缘奖励系统的神经适应性改变，导致与成瘾相关的行为。我们最近表明，酒精上调了成纤维细胞生长因子 2（FGF2）在背内侧纹状体（DMS）或大鼠和小鼠中的表达，反过来，FGF2 增加了酒精的消耗。在这里，我们表明，长期饮酒也会增加 FGF2 受体 FGFR1 在 DMS 中的表达。重要的是，选择性受体拮抗剂 FGFR1 活性的抑制通过全身或直接进入 DMS 减少酒精摄入。我们进一步表明，FGF2-FGFR1 对酒精饮用的影响是通过激活 PI3K 细胞内信号通路介导的，为这种效应的机制提供了一个见解。
