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

Abstract

Background: Glucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.

Methods: In the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.

Findings: In male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.

Interpretation: Altogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.

Funding: Swedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.

Keywords: Addition; Dopamine; GLP-1; Gut-brain axis; Nucleus accumbens; Reward.

Fig. 1

Semaglutide treatment decreases alcohol intake and prevents relapse drinking in male and female rats. (A) Schematic illustration of the alcohol drinking experiment, in which semaglutide was injected acutely at three alcohol drinking sessions (S1, S4, S7). (B) In male rats, semaglutide (0.026 mg/kg, n = 12) reduces the overall alcohol intake compared to vehicle (n = 12); a reduction specifically evident at alcohol drinking session 1 and 7. (C) As further shown in males, in comparison to vehicle (n = 12) semaglutide (0.052 mg/kg, n = 12) decreases alcohol intake at each treatment session. Similarly, compared with vehicle (n = 12 in each test) both semaglutide doses, (D) 0.026 mg/kg (n = 12) and (E) 0.052 mg/kg (n = 12), reduce alcohol intake at each treatment session in female rats. (F) Schematic illustration of the alcohol drinking experiment, in which semaglutide was injected repeatedly at five subsequent alcohol drinking sessions (S1, S2, S3, S4, S5). (G) In this design, repeated semaglutide (0.026 mg/kg, n = 12) treatment reduces alcohol intake in male rats compared to vehicle (n = 12). (H) Additionally, in comparison to vehicle (n = 12), repeated semaglutide treatment (0.026 mg/kg, n = 12) lowered alcohol intake in female rats. This decline is evident at drinking session 2, 3 and 4 in males, and at each session in females. (I) Schematic illustration of the alcohol drinking experiment, in which the effect of semaglutide on relapse-like drinking after alcohol withdrawal was tested. Semaglutide is injected 60 min prior to alcohol exposure, thereafter the rats consumed alcohol for 48 h. (J) The % increase in alcohol intake from baseline (dotted line) is reduced by semaglutide. Specifically, alcohol withdrawal induces a relapse drinking (t (13) = 3.29, P = 0.0059, paired t-test, n = 14) in male rats, and semagltuide blocks the relapse-like drinking (t (14) = 2.67, P = 0.0187, paired t-test, n = 15) (data not shown). (K) Additionally, semaglutide decreases the alcohol intake 24 and 48 h after treatment. (L) In female rats, semaglutide reduces the % increase in alcohol intake from baseline (dotted line). Indetail, alcohol withdrawal trends to cause relapse-like drinking (t (14) = 1.18, P = 0.1287, paired t-test, n = 14) in female rats and this was prevented by semaglutide treatment (t (15) = 4.65, P = 0.0003, paired t-test, n = 16) (data not shown). (M) The reduced alcohol intake is also evident 24 and 48 h after semaglutide treatment. Overall interaction effect (B–E) and overall treatment effect (G–H) from two-way ANOVA with repeated measures is stated in figure. J–K data were analysed with a paired t-test and K-L wih an unpared t-test. Experiments were not replicated. Data are presented as mean ± SEM, significant data are illustrated by ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Syringe indicates time of injection.

Fig. 2

Semaglutide reduces the intake of food in alcohol drinking male and female rats. In male rats, semaglutide at both doses, (A) 0.026 mg/kg (n = 12) and (B) 0.052 mg/kg (n = 12) reduce the overall food intake compared to vehicle (n = 12 in each test); a reduction evident at each treatment session. (C) Compared to vehicle (n = 12), repeated semaglutide treatment (0.026 mg/kg) lowers the overall intake of food in male rats. This decline is found at each treatment session. Similarly, compared with vehicle (n = 12 in each test) both semaglutide doses, (D) 0.026 mg/kg (n = 12) and (E) 0.052 mg/kg (n = 12), decrease food intake at each treatment drinking session in female rats. (F) Additionally, in comparison to vehicle (n = 12), repeated semaglutide treatment (0.026 mg/kg, n = 12) decreases the food intake in females, a reduction evident at alcohol drinking session 1, 2, 3 and 5. Overall interaction effect (A–F) from two-way ANOVA with repeated measures is stated in the figure. Experiments were not replicated Data are presented as mean ± SEM, significant data are illustrated by ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Syringe indicates time of injection.

Fig. 3

In male mice, semaglutide attenuates the alcohol-induced locomotor stimulation and dopamine release in nucleus accumbens shell as well as decreases the consumption of rewarding foods. (A) Compared to vehicle (n = 12), alcohol (n = 18) causes a locomotor stimulation, and acute administration of semaglutide (0.026 mg/kg, n = 15) blocks the alcohol-induced locomotor stimulation in male mice. Additionally, semaglutide (n = 12) does not affect the activity of mice per se. (data analysed with one-way ANOVA) (B) In comparison to vehicle (n = 12), alcohol (n = 11) enhances the dopamine levels in nucleus accumbens shell of male mice. Semaglutide (n = 8) attenuates the ability of alcohol to increase dopamine in male mice, while it (n = 9) alone does not alter the dopamine levels. Data analysed with a two-way ANOVA with repeated measures. Together these findings indicate that semaglutide supresses the reward-like behaviours associated with alcohol of male mice. In further support for semaglutide's ability to suppress reward, it reduces the 4-h intake of (C) peanut butter (n = 12 per group) and (D) Nutella (n = 8 per group) in male mice. Data analysed with unpaired t-test. These findings have led to the hypothesis that semaglutide acts within the nucleus accumbens shell. (E) Illustration of the selected part of nucleus accumbens shell where the fluorescently labeled semaglutide (CY3-semaglutide) is detected. After systemic administration, CY3-semaglutide is detected in nucleus accumbens shell of alcohol drinking (F) male and (G) female rats. (H) This signal not found in alcohol drinking rats injected with vehicle. Experiments were not replicated. Data are presented as mean ± SEM, significant data are illustrated by ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. +P < 0.05, ++P < 0.001 when comparing vehicle-alcohol versus semaglutide-alcohol in the microdialysis experiment.

Fig. 4

Semaglutide enhances dopamine metabolism in nucleus accumbens when alcohol is onboard. The in vivo microdialysis experiment reveals that the (A) DOPAC and (B) HVA levels in nucleus accumbens (NAc) shell are higher in male mice treated with the combination of semaglutide and alcohol compared to those treated with only alcohol (n = 12 for vehicle–vehicle, n = 18 for vehicle-alcohol, n = 12 for semaglutide-vehicle, n = 15 for semaglutide-alcohol; two-way ANOVA with repeated measures). These results indicate that semaglutide enhances the metabolism of dopamine when alcohol is onboard. In support, the NAc gene expression of (C) MAOA and (D) COMT, but not (E) MAOB and (F) DAT, is higher in male mice treated with both semaglutide and alcohol compared to those treated with alcohol (n = 5 for both treatment groups, unpaired t-test). Experiments were not replicated. Data are presented as mean ± SEM, significant data are illustrated by ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 in comparison to vehicle treatment; +P < 0.05, ++P < 0.01, +++P < 0.001 when comparing alcohol treatment to the combination of semaglutide and alcohol.