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Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice

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Abstract

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1’s role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

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Data Availability

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Funding

This work was supported by National Natural Science Foundation of China (81771193, 81974169, 82171226), National Key R&D Program of China (2019YFC1712104), and Postgraduate independent Innovation Project of Academy of Medical Sciences of Zhengzhou University.

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Authors and Affiliations

  1. Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Weizhen Liu, Ziliang Wang, Wang Wang, Zhiju Wang & Ying Xing

  2. The Academy of Medical Sciences of Zhengzhou University, Zhengzhou, 450001, Henan, China

    Weizhen Liu, Ziliang Wang & Wang Wang

  3. Henan Academy of Innovation in Medical Science, XinZheng, 451100, Henan, China

    Christian Hölscher

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  1. Weizhen Liu
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  2. Ziliang Wang
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  3. Wang Wang
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  4. Zhiju Wang
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  5. Ying Xing
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  6. Christian Hölscher
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Contributions

WL, ZW designed the experiments and analyzed the data. WL prepared the manuscript. Authors WW, ZW, YX, CH provided comments and revised the manuscript, and authors YX, CH were the supervisors. All authors approved the final manuscript.

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Correspondence to Ying Xing or Christian Hölscher.

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This study protocol was reviewed and approved by the Ethics committee of Zhengzhou university, approval number ZZUIRBGZR2017-459.

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Liu, W., Wang, Z., Wang, W. et al. Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice. Neurochem Res 49, 1061–1075 (2024). https://doi.org/10.1007/s11064-023-04093-6

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