Involvement of Fibroblast Growth Factor-2 in alcohol use disorder

该建议的工作假设是，过量的酒精暴露诱导黑质纹状体系统中纤维母细胞生长因子2 （FGF2）依赖的神经适应，导致多巴胺能系统功能异常，并导致强迫性、失控的饮酒和酒精成瘾表型的发展。本项目的总体目标是阐明FGF2与饮酒行为相互作用的机制，即酒精调节FGF2表达，FGF2调节饮酒行为。我们将更好地了解a)哪些不同的FGF2亚型，b)它们如何影响控制成瘾相关行为的中脑纹状体多巴胺能通路，以及酒精暴露对该系统的影响。特别地，我们将处理四个目标来表征成瘾相关场景中不同参与者在生化、分子、形态和行为参数方面的相互作用，即黑质纹状体系统中FGF2系统、多巴胺能系统和其他FGF2相关的酒精消耗基因。首先，我们的目标是确定酒精消耗过程中FGF2及其靶细胞的异构体、细胞来源和定位。其次，我们计划分析酒精消耗驱动中脑纹状体系统中fgf2相关基因的表达。第三，将阐明与FGF2增加相关的多巴胺能神经元的长期形态学变化。最后，我们将测试FGF2系统的抑制是否会阻止这些神经适应并减少酒精消耗和复发，作为治疗酒精使用障碍的潜在药物治疗策略。

The working hypothesis of the proposal is that excessive alcohol exposure induces fibroblast growth factor 2 (FGF2)-dependent neuroadaptations in the nigrostriatal system, leading to abnormal function of the dopaminergic system, and to the development of a compulsive, out-of-control drinking and alcohol addiction phenotypes. The general objective of the proposed project is to elucidate the mechanisms, by which FGF2 interacts with alcohol-drinking behaviors, i.e. alcohol regulates FGF2 expression, and FGF2 regulates alcohol-drinking behaviors. We will gain better understanding on a) which of the different FGF2 isoforms and b) how they affect the midbrain-striatum dopaminergic pathways that control behaviors related to addiction, as well as the effects of alcohol exposure on this system. In particular, we will treat four objectives to characterize the interaction of the different players in the addiction-related scenario with regard to biochemical, molecular, morphological, and behavioral parameters, i.e. the FGF2 system, the dopaminergic system, and other FGF2-related alcohol consumption genes in the nigrostriatal system. First, we aim to determine the isoforms, cellular source and localization of FGF2 and its target cells during alcohol consumption. Second, we plan to analyze the FGF2-related gene expression in the midbrain-striatal system driven by alcohol consumption. Third, long-lasting morphological changes in dopaminergic neurons related to the FGF2 increase will be elucidated. Finally, we will test whether suppression of the FGF2 system prevents these neuroadaptations and reduces alcohol consumption and relapse, as a potential pharmacotherapeutic strategy to treat alcohol use disorder.