Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice

RationaleAlcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce.ObjectivesTo assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice.MethodsMale and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 mu g/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group.ResultsExendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects.ConclusionsIn male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.

Automated summary

This study aimed to evaluate the effect of GLP-1 receptor agonist exendin-4 on alcohol-seeking behavior, compare its potency and efficacy in reducing alcohol seeking versus alcohol intake, and examine the differences between male and female mice. The results showed that exendin-4 effectively suppressed alcohol seeking in male mice but had less pronounced effects in female mice. This study highlights the importance of including both sexes in further investigations into GLP-1 receptor agonists.