Department of Pharmaceutical Bioscience, Uppsala University, Box 591, SE-75124, Uppsala, Sweden.
Department of Neuroscience, Uppsala University, Box 593, SE-75124, Uppsala, Sweden.
Mol Neurobiol. 2017 Oct;54(8):6225-6234. doi: 10.1007/s12035-016-0157-z. Epub 2016 Oct 5.
Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.
酒精滥用与应激、情绪和奖励脑回路的失调有关。这种关联的一个候选关键中介物是 FK506 结合蛋白（FKBP5），它是糖皮质激素受体的负调节剂。本研究的目的是进一步了解 FKBP5/FKBP5 相关基因在早期社会关系和饮酒行为之间的关系中的作用。研究了母鼠分离和自愿饮酒对幼鼠大脑中 Fkbp5 表达的影响，而功能性 FKBP5 单核苷酸多态性 rs1360780 基因型与亲子关系对问题饮酒的相互作用效应在年轻成人中进行了研究。在大鼠中，母鼠分离和酒精摄入以区域依赖性和相反的方式影响伏隔核和腹侧被盖区（奖励系统的核心区域）中 Fkbp5 的表达。边缘皮层中的 Fkbp5 表达受母鼠分离和酒精摄入的综合影响。在人类中，在儿童与父母关系不佳的情况下，TT 基因型与问题饮酒行为有关。这些发现表明，中脑边缘多巴胺能区域的 Fkbp5 表达与早期生活应激介导的对酒精摄入的敏感性有关，并且 FKBP5 基因型与亲子关系相互作用影响饮酒。这些发现首次指出 FKBP5 在酒精滥用倾向中的作用，并呼吁开展研究潜在的分子机制，以确定潜在的药物靶点。
