Mechanism of Action of the Glucagon-like Peptide-1 analog Exendin-4 in the Reward System – A Preclinical Study in the Drug Addiction Field

Abstract

Background: Alcohol use disorder is a great concern for public health and current pharmacological treatment is not sufficient. Over the last years, there has been a growing interest in the role of gut hormones in drug addiction. Glucagon-like peptide 1 (GLP-1), also acting as a neuropeptide, is one of these hormones in focus. Preclinical studies have shown that GLP-1 receptor agonists can reduce alcohol intake, attenuate alcohol-related behaviors and counter the ability of alcohol to increase dopamine levels in the nucleus accumbens (NAc), however, the mechanism of action is unknown. This study aims to elucidate how the GLP-1 analog exendin-4 acts in the reward system, when systemically administered. Methods: Male Wistar rats were administered an acute systemic injection of exendin-4 or vehicle, and samples of extracellular fluid from the NAc shell were collected using a microdialysis system. The samples were analyzed in an HPLC system to determine extracellular concentrations of the neurotransmitters glutamate, serine, glycine, taurine, beta-alanine and GABA, all involved in the reward process. The levels after injection were compared between treatment group and control group. Result: Exendin-4 significantly decreased the levels of serine, glycine and taurine in the NAc shell over time, compared to vehicle. No difference between treatments was found for glutamate. Conclusions: Serine, glycine and taurine are all agonists to the glycine receptor and previous studies have shown that activation of the glycine receptor in the NAc is crucial for alcohol to elevate the dopamine levels in the NAc. In this study we showed that exendin-4 lowers the levels of these neurotransmitters, thus forming the hypothesis that the drug prevents alcohol to activate the reward system through reduced glycine receptor activation in the NAc.