The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory...

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F_3,28  = 6.52, p = 0.002; oral alcohol, fixed dose: F_7,75.94  = 5.08, p < 0.001; intravenous alcohol, variable dose: F_4,37.03  = 20.72, p < 0.001; intravenous alcohol, fixed dose: F_4,13.92  = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F_1,21  = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F_1,20  = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.