Liraglutide reduces alcohol consumption, anxiety, memory impairment, and synapse loss in alcohol dependent mice

Abstract

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. Additionally, the underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on synaptic morphology and transmission in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the emotion and memory ability of alcohol-withdrawal mice. 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 water maze, open field, and elevated plus maze paradigms. Synaptic morphology in the mPFC and HP were assessed via Golgi staining and Western Blot analysis. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01). 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 anxietyinduced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions.