Activation of glucagon-like peptide-1 receptors reduces the acquisition of aggression-like behaviors in male mice

Abstract

Aggression is a complex social behavior, which is provoked in the defense of limited resources including food and mates. Recent advances show that the gut-brain hormone ghrelin modulates aggressive behaviors. As the gut-brain hormone glucagon-like peptide-1 (GLP-1) reduces food intake and sexual behaviors its potential role in aggressive behaviors is likely. Therefore, we investigated a tentative link between GLP-1 and aggressive behaviors by combining preclinical and human genetic-association studies. The influence of acute or repeated injections of a GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex4), on aggressive behaviors was assessed in male mice exposed to the resident-intruder paradigm. Besides, possible mechanisms participating in the ability of Ex4 to reduce aggressive behaviors were evaluated. Associations of polymorphisms in GLP-1R genes and overt aggression in males of the CATSS cohort were assessed. In male mice, repeated, but not acute, Ex4 treatment dose-dependently reduced aggressive behaviors. Neurochemical and western blot studies further revealed that putative serotonergic and noradrenergic signaling in nucleus accumbens, specifically the shell compartment, may participate in the interaction between Ex4 and aggression. As high-fat diet (HFD) impairs the responsiveness to GLP-1 on various behaviors the possibility that HFD blunts the ability of Ex4 to reduce aggressive behaviors was explored. Indeed, the levels of aggression was similar in vehicle and Ex4 treated mice consuming HFD. In humans, there were no associations between polymorphisms of the GLP-1R genes and overt aggression. Overall, GLP-1 signaling suppresses acquisition of aggressive behaviors via central neurotransmission and additional studies exploring this link are warranted.

Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats

“…Total RNA was extracted, purified and amplified as done before. 32 , 50 The expression of the MAOA , MAOB , COMT and DAT genes (ThermoFisher, MAOA; Mm00558004_m1, MAOB; Mm00555412_m1, COMT; Mm00514377_m1, DAT; Mm00438396_m1; Catalogue number 4331182) was normalized to the geometric mean of beta-actin (ThermoFisher, Mm01205647_g1; Catalogue number 4331182). Thereafter, the expression COMT, MAOA , MAOB and DAT genes, were expressed as fold change relative to vehicle-alcohol.…”

Antismoking agents do not contribute synergistically to semaglutide’s ability to reduce alcohol intake in rats

“…A finding in contrast to other behaviors in which HFD blunts the treatment outcome of GLP-1R agonists ( Williams et al, 2011 ; Duca et al, 2013 ; Mella et al, 2017 ; Williams et al, 2018 ; Al Helaili et al, 2020 ; Vestlund et al, 2022 ). Specifically, a similar HFD design blunts the ability of exendine-4, another GLP-1R agonist, to reduce aggression ( Vestlund et al, 2022 ). Furthermore, since we have observed a significant decrease in alcohol consumption following HFD exposure, further investigations are needed to determine whether there is an additive effect between adjusted HFD designs and semaglutide.…”

“…On the other hand, HFD does not influence the ability of semaglutide to reduce alcohol intake in neither male nor female alcohol exposed rats. A finding in contrast to other behaviors in which HFD blunts the treatment outcome of GLP-1R agonists (Williams et al, 2011;Duca et al, 2013;Mella et al, 2017;Williams et al, 2018;Al Helaili et al, 2020;Vestlund et al, 2022). Specifically, a similar HFD design blunts the ability of exendine-4, another GLP-1R agonist, to reduce aggression (Vestlund et al, 2022).…”

“…In the HFD experiment, peanut butter (Green Choice; Coop, Gothenburg, Sweden) was used as HFD. While previous studies have used different designs to decrease alcohol drinking ( Sirohi et al, 2017a ; Sirohi et al, 2017b ; Villavasso et al, 2019 ; Coker et al, 2020 ), another design was used as this design previously has been shown to blunt the ability of another GLP-1R agonist to reduce aggressive behaviors ( Vestlund et al, 2022 ).…”

Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

“…Areas were pooled in groups of three in order to ensure sufficient amount of RNA to reliably measure expression. Total RNA was extracted, purified and amplified as done before 29,31,32 . The expression of the leap2 gene (ThermoFisher, Mm00461982) was normalized to the geometric mean of betaactin (ThermoFisher, Mm01205647).…”