Effects of chronic ethanol consumption on brain GLP-1R gene expression in mice and humans

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as a promising therapeutic option for alcohol use disorder (AUD), yet the underlying mechanisms and neurocircuitry involved remain unclear. This study aimed to analyze GLP-1R gene expression changes in brain regions associated with alcohol's effects, including the prefrontal cortex (PFC), nucleus accumbens (NAc), and hippocampus (HIP), in mice following 42 days of voluntary ethanol consumption (VEC; 10% v/v) and postmortem samples from 18 patients with AUD. Additionally, we examined the expression of OPRM1 (mu-opioid receptor) and BDNF (brain-derived neurotrophic factor), key targets related to alcohol intake and reward, in the NAc and HIP, respectively. GLP-1R gene expression was significantly reduced in all brain regions of ethanol-exposed mice and AUD patients. These reductions paralleled decreased OPRM1 and BDNF expression in the NAc and HIP, respectively. Pearson and Spearman correlation analyses revealed no significant associations between gene expression and age, RIN, pH, postmortem interval (PMI), body mass index (BMI), smoking status, age of onset of alcohol use, or years of drinking. In summary, chronic alcohol consumption in humans or mice was associated with decreased GLP-1R gene expression in brain regions involved in the reinforcing effects of ethanol. These findings open new avenues for further research into how this emerging receptor could serve as a potential biomarker and therapeutic target in AUD.