FGF21 Analogue PF-05231023 on Alcohol Consumption and Neuronal Activity in the Nucleus Accumbens

Cooley, B. J.; Occelli Hanbury-Brown, C. V.; Choi, E. A.; Heller, W. A.; Lim, A. W.; Lawrence, A. J.; Haber, P. S.; McNally, G. P.; Millan, E. Z.

doi:10.1101/2024.12.22.629996

bioRxiv · 10.1101/2024.12.22.629996

FGF21 Analogue PF-05231023 on Alcohol Consumption and Neuronal Activity in the Nucleus Accumbens

Cooley, B. J.·Occelli Hanbury-Brown, C. V.·Choi, E. A.·Heller, W. A.·Lim, A. W.·Lawrence, A. J.·Haber, P. S.·McNally, G. P.·Millan, E. Z.

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Abstract

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. 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 GLP-1 agonist Exendin-4. 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. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours 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 appear to involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons.

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Cooley, B. J., Occelli Hanbury-Brown, C. V., Choi, E. A., Heller, W. A., Lim, A. W., Lawrence, A. J., Haber, P. S., McNally, G. P., Millan, E. Z.. 2024-12-23. FGF21 Analogue PF-05231023 on Alcohol Consumption and Neuronal Activity in the Nucleus Accumbens. https://doi.org/10.1101/2024.12.22.629996

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