Effects of glucagon-like peptide 1 analogs on alcohol intake in alcohol-preferring vervet monkeys

Abstract

Background: Preclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated.

Methods: We performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11-12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 μg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout.

Results: Liraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle.

Conclusions: The present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.

Keywords: Alcohol use disorder; Exendin-4; GLP-1; Liraglutide; Non-human primate; Pharmacotherapy.

Fig. 1. Diagram of the experimental designs

Schematic representation of the experimental phases for exenatide (a) and liraglutide (b). For experiment phase, open boxes represent no treatment, grey boxes represent weekly (exenatide) or daily (liraglutide) administration of drug or vehicle. For access to alcohol, black bars represent daily 4h access, open bars represent no access. Arrows represent blood sampling.

Fig. 2. Intake of alcohol and water at baseline

Daily alcohol and water intake averaged over the baseline assessment period for the exenatide study (a,b) and the liraglutide study (c,d). Ordinates: alcohol intake in g/kg/4h (top), water intake in ml/kg/4h (bottom). Data are group means, bars represent s.e.m. n=12, except for the exenatide group, n=11.

Fig. 3. Effect of exenatide on intake of alcohol and water

Daily alcohol (a) and water (b) intake during the exenatide treatment. Abscissa: days of alcohol access after initiation of the GLP-1 receptor agonist treatment. Ordinates and group sizes as in Fig. 2. *p < 0.05 exenatide vs. vehicle ANOVA main effect.

Fig. 4. Effect of exenatide and liraglutide on plasma alcohol levels

Plasma alcohol levels from blood taken immediately after a 4h drinking session, taken the last liraglutide/vehicle treatment day, and Wednesday of the last exenatide/vehicle treatment week. *p < 0.05. Ordinates: plasma alcohol in mg/ml. Group sizes as in Fig. 2. Exe: exenatide, Veh: vehicle, Lira: liraglutide. *p < 0.05 liraglutide vs. vehicle.

Fig. 5. Effect of liraglutide on intake of alcohol and water

Daily alcohol (a) and water (b) intake during the liraglutide treatment and washout. Abscissa, days of alcohol access after initiation of the GLP-1 receptor agonist treatment. Ordinates and group sizes as in Fig. 2. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle.