Cooley Bart J, Occelli Hanbury-Brown Cassandra V, Choi Eun A, Heller Willow A, Lim Alyssa W, Lawrence Andrew J, Haber Paul S, McNally Gavan P, Millan E Zayra
School of Psychology, UNSW Sydney, Sydney, NSW, Australia.
Florey Institute of Neuroscience and Mental Health, Parkville, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
Neuropsychopharmacology. 2025 May 26. doi: 10.1038/s41386-025-02133-z.
Fibroblast growth factor 21 (FGF21) is a liver-derived hormone known to suppress alcohol consumption in mice and non-human primates. However, the role of FGF21 in modulating environmental and behavioural factors driving alcohol consumption-such as cue-driven responses and effortful actions to obtain alcohol-and its effects on neural activity related to consumption, remain unclear. Here, we evaluated the impact of PF-05231023, a long-acting FGF21 analogue, across multiple dimensions of alcohol consumption and motivation and examined consumption-related activity in the nucleus accumbens. PF-05231023 reduced alcohol intake and preference in a dose- and sex-specific manner; diminished approach behaviours following an alcohol but not sucrose cue; and decreased lever-pressing under a progressive-ratio schedule, both alone and when combined with the Glucagon-like peptide-1 (GLP-1) agonist Exendin-4; it did not reduce lever-pressing for sucrose in alcohol-naïve mice. Additionally, PF-05231023 altered the microstructure of alcohol consumption by shortening drinking bouts and increased the recruitment of nucleus accumbens (Acb) neurons associated with bout termination as determined by micro-endoscopy of GCaMP7f. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours without impacting natural reward and that targeting FGF21 signaling in combination with GLP-1 agonists may enhance therapeutic efficacy. Mechanistically, the observed reductions in alcohol consumption following PF-05231023 may involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons.
成纤维细胞生长因子21（FGF21）是一种肝脏衍生激素，已知可抑制小鼠和非人类灵长类动物的酒精摄入量。然而，FGF21在调节驱动酒精摄入的环境和行为因素（如线索驱动反应和获取酒精的努力行为）及其对与饮酒相关的神经活动的影响方面的作用仍不清楚。在这里，我们评估了长效FGF21类似物PF-05231023在酒精摄入和动机的多个维度上的影响，并检查了伏隔核中与饮酒相关的活动。PF-05231023以剂量和性别特异性方式减少了酒精摄入量和偏好；减少了酒精线索而非蔗糖线索后的趋近行为；并降低了在累进比率时间表下的杠杆按压次数，无论是单独使用还是与胰高血糖素样肽-1（GLP-1）激动剂艾塞那肽-4联合使用时；它并没有减少未接触过酒精的小鼠对蔗糖的杠杆按压次数。此外，PF-05231023通过缩短饮酒时间改变了酒精消费的微观结构，并增加了与饮酒终止相关的伏隔核（Acb）神经元的募集，这是通过对GCaMP7f进行显微内窥镜检查确定的。这些发现表明，PF-05231023广泛抑制了由酒精驱动的行为，而不影响自然奖励，并且靶向FGF21信号通路与GLP-1激动剂联合使用可能会提高治疗效果。从机制上讲，可以观察到PF-05231023后酒精摄入量的减少可能涉及酒精适口性的降低以及来自Acb神经元不同亚群的神经元活动的调节。
