Abstract
Given the limited efficacy of available pharmacotherapies for treatment of alcohol use disorder (AUD), the need for new medications is substantial. Preclinical studies have shown that acute administration of glucagon-like peptide-1 receptor (GLP-1R) agonists inhibits various ethanol-related behaviours, indicating this system as a potential target for AUD. However, the effects of long-term systemic treatment of GLP-1R agonists on ethanol intake in male and female rodents are to date unknown. Therefore, we investigated the effects of 9 or 5 weeks of once weekly administration of dulaglutide, a long-acting GLP-1R agonist, on ethanol intake in male and female rats. The ethanol intake during treatment discontinuation was also monitored. In an initial attempt to identify preliminary underlying mechanisms, the effects of 9 weeks of once weekly dulaglutide treatment on monoaminergic signalling in reward-related areas were explored in both sexes. We found that 9 or 5 weeks of once weekly dulaglutide treatment reduced ethanol intake and preference in male and female rats. Following discontinuation of dulaglutide treatment, the decrease in ethanol consumption was prolonged in males, but not females. We demonstrated that 9 weeks of dulaglutide treatment differentially influenced monoaminergic signalling in reward-related areas of male and female rats. Collectively, these data imply that the GLP-1R attracts interest as a potential molecular target in the medical treatment of AUD in humans: more specifically, dulaglutide should be evaluated as a potential medication for treatment thereof.
Highlights
Despite alcohol use disorder (AUD) being a leading cause of mortality and morbidity[1,2], only four AUD pharmacotherapies are available
During baseline ethanol-drinking there were no differences in ethanol intake (F(2,42)=0.07, P = 0.9327, n = 15 per group) in male rats later subjected to vehicle, or either dose of dulaglutide (0.05 or 0.1 mg/kg)
And 4a, the ethanol consumption at ethanol-drinking session 33 was similar in rats previously treated with dulaglutide or vehicle for 5 weeks. In these ethanol-drinking rats which at session 33 were untreated for six weeks, there were no differences in the monoamines and their metabolites levels in the studied brain areas (Data and comprehensive statistical analysis are found in Supplementary Table 7 for males or Supplementary Table 8 for females, n = 10 for all groups) in rats previously treated with dulaglutide or vehicle. In both male and female rats 9 or 5 weeks of once weekly injections with dulaglutide decreased ethanol intake, which was accompanied by a reduction in ethanol preference
Summary
Despite alcohol use disorder (AUD) being a leading cause of mortality and morbidity[1,2], only four AUD pharmacotherapies are available. As all of these display varied efficacy[3,4], there is a substantial need to identify new medications treating AUD. The gut-brain peptide, glucagon-like peptide-1 (GLP-1) lowers blood glucose levels and inhibits glucagon secretion GLP-1 receptor (GLP-1R) activation decreases feeding behaviours, appetite and body weight[9]. Liraglutide, another GLP-1R agonists, was approved as an anti-obesity medication Liraglutide, another GLP-1R agonists, was approved as an anti-obesity medication (for review see ref. 10)
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