Activation of GLP-1R ameliorates alcohol withdrawal induced anxiety-like behavior by regulating neuronal mitochondrial quality control.

INTRODUCTION

Alcohol use disorder (AUD) is a specific psychological state induced by repeated heavy drinking, and withdrawal symptoms such as anxiety are closely related to relapse after withdrawal. While neuronal damage caused by alcohol is considered a significant precipitating factor for withdrawal-induced anxiety, the underlying molecular mechanisms remain unclear.

METHODS

In this study, we established a mouse model of alcohol withdrawal through 3 months of chronic ethanol exposure (CEE) followed by withdrawal. Mice were treated with semaglutide (0.03 mg/kg) via intraperitoneal injection and subjected to behavioral, biochemical, and morphological analyses.

RESULTS

Our results demonstrate that the glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide alleviates anxiety-like behaviors in CEE withdrawal mice and reverses the downregulation of GLP-1R and its downstream effector CREB in the mitochondria of prefrontal cortex (PFC) neurons. Enhancing the GLP-1R/CREB pathway regulates mitochondrial quality control, including fission, fusion, and mitophagy, to maintain mitochondrial function and ameliorate synaptic impairment.

DISCUSSION: These findings suggest that activation of GLP-1R ameliorates alcohol withdrawal-induced anxiety-like behaviors by regulating neuronal mitochondrial function, providing a potential therapeutic target for AUD.