The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

Abstract

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.

Keywords: Addiction; Endocrinology; Neuroscience.

Figure 1. Semaglutide reduces binge-like alcohol drinking in mice.

(A) Semaglutide reduced alcohol intake (g/kg of body weight) in mice drinking sweet alcohol. Males (n = 8); females (n = 7). (B) Semaglutide reduced alcohol intake (g/kg of body weight) in mice drinking unsweet alcohol; female mice drank significantly more alcohol than males. Males (n = 8); females (n = 8). (C) Semaglutide reduced fluid intake (mL/kg of body weight) in mice drinking a sweet solution not containing alcohol. Males (n = 8); females (n = 6). Separate cohorts of mice were used to test the effects of semaglutide on the consumption of each drinking solution. Data are expressed as mean ± SEM and were analyzed using 2-way repeated-measures ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus vehicle. Individual values are presented for males (♂) and females (♀).

Figure 2. Semaglutide reduces drinking of noncaloric and caloric solutions not containing alcohol in mice.

(A and B) Semaglutide reduced fluid intake (mL/kg of body weight) in mice drinking water or a saccharin-sweetened noncaloric solution. (C and D) Semaglutide reduced calorie intake (Kcal/kg of body weight) in mice drinking an unsweet carbohydrate (maltodextrin) solution or an unsweet fat (corn oil) emulsion. Separate cohorts of mice were used to test the effects of semaglutide on the consumption of each drinking solution (n = 8, 4 per sex, per condition). Data are expressed as mean ± SEM and were analyzed using 1-way repeated-measures ANOVA. **P < 0.01, ***P < 0.001, ****P < 0.0001 versus vehicle. Individual values are presented for males (♂) and females (♀).

Figure 3. Semaglutide reduces operant alcohol self-administration in rats.

(A) Semaglutide dose-dependently reduced sweet alcohol self-administration (binge-like drinking) in rats. (B) Semaglutide did not reduce water self-administration in nondependent rats (significant Dose effect, but no significant post hoc differences); female nondependent rats self-administered significantly more water than males. Nondependent males (n = 10); nondependent females (n = 10). (C) Semaglutide only at the highest dose (0.1 mg/kg) reduced unsweet alcohol self-administration (dependence-induced drinking) in rats. (D) Semaglutide had no effect on water self-administration in alcohol-dependent rats; male dependent rats self-administered significantly more water than females. Dependent males (n = 11); dependent females (n = 11). Data are expressed as mean ± SEM and were analyzed using 2-way repeated-measures ANOVA. **P < 0.01, ****P < 0.0001 versus vehicle. Individual values are presented for males (♂) and females (♀).

Figure 4. Semaglutide increased GABA transmission in central nucleus of the amygdala (CeA) neurons from alcohol-naive rats but had mixed effects in alcohol-dependent rats.

(A) Representative spontaneous inhibitory postsynaptic current (sIPSC) traces during baseline control (upper panel) conditions and during superfusion of 100 nM semaglutide (lower panel). (B–E) Bar charts summarize the effects of semaglutide (100nM) on sIPSC frequencies (B), amplitudes (C), rise times (D), and decay times (E) from 10 to 15 neurons from alcohol-naive (gray bars) and alcohol-dependent rats (red bars). Data are expressed as mean ± SEM. Differences between semaglutide and baseline control conditions (dashed lines) were analyzed using 1-sample Student’s t tests (**P < 0.01). Differences of semaglutide effects on selected parameters between alcohol-naive and alcohol-dependent rats were analyzed using unpaired Student’s t tests (^$P < 0.05). Data were generated from 6 alcohol-naive and 8 alcohol-dependent rats, from 2 separate chronic, intermittent, alcohol vapor exposure cohorts.

Figure 5. Semaglutide increased GABA transmission in pyramidal neurons in layer 5 of the infralimbic cortex (ILC) from alcohol-naive rats but had mixed effects in alcohol-dependent rats.

(A) Representative spontaneous inhibitory postsynaptic currents (sIPSC) traces during baseline control (upper panel) conditions and during superfusion of 100 nM semaglutide (lower panel). (B–E) Bar charts summarize the effects of semaglutide (100nM) on sIPSC frequencies (B), amplitudes (C), rise times (D), and decay times (E) from 9 to 12 neurons from alcohol-naive (gray bars) and alcohol-dependent rats (red bars). Data are expressed as mean ± SEM. Differences between semaglutide and baseline control conditions (dashed lines) were analyzed using 1-sample Student’s t tests (**P < 0.01). Differences of semaglutide effects on selected parameters between alcohol-naive and alcohol-dependent rats were calculated using unpaired Student’s t tests (^$P < 0.05). Data were generated from 5 alcohol-naive and 7 alcohol-dependent rats, from 2 separate chronic, intermittent, alcohol vapor exposure cohorts.