Alcohol-mediated behaviours and the gut-brain axis; with focus on glucagon-like peptide-1

Abstract

The neurochemical mechanisms that regulate development of alcohol use disorder (AUD) are complex, and gut-brain peptides were recently pinpointed as novel modulators. Gut-brain peptides, such as glucagon-like peptide-1 (GLP-1), are well known for their ability to regulate food intake and appetite. GLP-1 also controls glucose homeostasis, which lead to the approval of GLP-1 receptor agonists for treatment of diabetes type II. These pharmacotherapies, including exenatide/exendin-4(Ex4) and liraglutide, have also been tested in various animal modes of AUD. In mice, Ex4 attenuates the acute behavioural responses to alcohol. Rat studies additionally show that Ex4 reduces the intake and the intravenous operant self-administration of alcohol and decreases the motivation to consume alcohol. Further studies established that Ex4 modulates alcohol-mediated behaviours via activation of GLP-1 receptors in reward related areas and an area of the hindbrain. In rodents, liraglutide reduces withdrawal symptoms of alcohol, prevents acute alcohol to activate the mesolimbic dopamine system, and in turn reduces various alcohol drinking behaviours. Supportively, liraglutide decreases alcohol intake in vervet monkeys. Finally, another GLP-1 receptor agonist, AC3174, counteracts relapse drinking to alcohol. Of clinical relevance is the case-control study which reveals associations between polymorphisms in the GLP-1 receptor gene and AUD. Furthermore, a polymorphism in the GLP-1 receptor gene is associated with enhanced intravenous self-administration of alcohol in social drinkers and higher response in globus pallidus following high monetary reward. Collectively, these data provide evidence that up-coming clinical trials should evaluate the effect of these GLP-1 receptor agonists on alcohol intake in patients with AUD.

Keywords: Addiction; Appetite-regulation; Dopamine; Endocrine signals; Ethanol; Reinforcement.