Claudia Díaz‑Megido & Morgane Thomsen
Glucagon like peptide-1 has shown promising pre-clinical evidence as a target for alcohol use disorder. Ongoing research is assessing the impact on alcohol-related behaviours, paving the way for translation clinical trials. Díaz‑Megido and Thomsen assessed the effects of acute Exendin-4 (a short acting glucagon like peptide-1 agonist) on alcohol self-administration and cue-induced reinstatement of alcohol seeking in mice. The authors found sex-dependent, short-term effects of exendin-4 on cue-induced reinstatement. After training mice to lever press for 20% alcohol and then extinguishing this lever press behavior, administration of 1.8ug/kg or 3.2ug/kg of exendin-4 abolished cue-induced reinstatement of alcohol seeking in male but not female mice. Interestingly, the effect of Exendin-4 was transient because it significantly reduced active lever presses in the first hour but not the second hour of the reinstatement session. This relatively short-lasting effect contrasts with the longer lasting effects of similar doses of Exendin-4 on ingestive behaviour, implying distinctions in the biological pathways effected. There were similar sex specific and transient effects of Exendin-4 on oral alcohol self-administration but the magnitude of the effect was smaller. Given these dissociable effects on reinforced oral alcohol self-administration and cue induced reinstatement (reinforced by water) the authors suggests that Exendin-4 may modulate the rewarding effects of alcohol or inhibitory control rather than satiety. The authors offer several possibilities for the apparent sex differences. For example, they note sex differences in the properties and expression of GLP-1 neurons that may underly differences in exendin-4 sensitivity. Additionally, they point towards literature which suggests the general blunting of effects of manipulations on self-administration in females compared to males. This study reveals compelling insights into the role of GLP-1 agonists in regulating operant alcohol-related behaviours. Intriguingly, it also highlights that the effects on operant behaviours may be sex-specific emphasising the need to consider sex-effects in future pre-clinical addiction research.
Blog written by: Bart Cooley
PhD Candidate, University of New South Wales