The glucagon-like peptide 1 analogue, exendin-4, attenuates the rewarding properties of psychostimulant drugs in mice

Abstract

Glucagon-like peptide 1 (GLP-1) is an incretine hormone that controls consummatory behavior and glucose homeostasis. It is released in response to nutrient ingestion from the intestine and production in the brain has also been identified. Given that GLP-1 receptors are expressed in reward areas, such as the nucleus accumbens and ventral tegmental area, and that common mechanisms regulate food and drug-induced reward we hypothesize that GLP-1 receptors are involved in reward regulation. Herein the effect of the GLP-1 receptor agonist Exendin-4 (Ex4), on amphetamine- and cocaine-induced activation of the mesolimbic dopamine system was investigated in mice. In a series of experiments we show that treatment with Ex4, at a dose with no effect per se, reduce amphetamine- as well as cocaine-induced locomotor stimulation, accumbal dopamine release as well as conditioned place preference in mice. Collectively these data propose a role for GLP-1 receptors in regulating drug reward. Moreover, the GLP-1 signaling system may be involved in the development of drug dependence since the rewarding effects of addictive drugs involves interferences with the mesolimbic dopamine system. Given that GLP-1 analogues, such as exenatide and liraglutide, are clinically available for treatment of type II diabetes, we propose that these should be elucidated as treatments of drug dependence.

Figure 1. Exendin-4 attenuates amphetamine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice.

(A) Amphetamine-induced (2 mg/kg IP) locomotor stimulation was attenuated by a single injection of Ex4 (2.4 µg/kg IP) (n=8 in each group; **P<0.01, one-way ANOVA followed by a Bonferroni post-hoc test). (B) First we demonstrated a significant effect of amphetamine (2 mg/kg IP) to increase dopamine release in comparison to vehicle treatment (time interval 40-120 minutes (P<0.001) and 140-160 minutes (P<0.05), Veh-Veh vs Veh-Amph). As shown in (B) pre-treatment with Ex4 (2.4 µg/kg IP) attenuated the amphetamine-induced increase in dopamine release compared to vehicle pre-treatment at time interval 40-8 minutes (*** < 0.001, Ex4-Amph compared to Veh-Amph treatment). The selected dose had no significant effect on accumbal dopamine release compared to vehicle treatment at any time interval (P>0.05, Veh-Veh vs Ex4-Veh). There was a significant difference in accumbal dopamine response in vehicle treated mice and Ex4-Amph treated mice at time interval 40-100 minutes (P>0.001). Arrows represent time points of injection of Ex4, vehicle and amphetamine. Data analyzed with a Two-way ANOVA followed by a Bonferroni post-hoc test (n=8 in each group) (C) The amphetamine-induced (2 mg/kg IP) condition place preference (CPP) was attenuated by an acute single IP injection of Ex4 (2.4 µg/kg IP) in mice (n=8 in each group, *P<0.05, unpaired t-test). All values represent mean ± SEM.

Figure 2. Exendin-4 attenuates cocaine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice.

(A) Cocaine-induced (10 mg/kg IP) locomotor stimulation was attenuated by a single injection of Ex4 (2.4 µg/kg IP) (n=8 in each group; **P<0.01 and **P<0.001, one-way ANOVA followed by a Bonferroni post-hoc test). (B) First we demonstrated a significant effect of cocaine (10 mg/kg IP) to increase dopamine release in comparison to vehicle treatment (40-140 minutes (P<0.001) and 160-180 minutes (P<0.01) Veh-Veh vs Veh-Coc). As shown in (B) pre-treatment with Ex4 (2.4 µg/kg IP) attenuated the cocaine-induced increase in dopamine release compared to vehicle pre-treatment (** < 0.001 and *** < 0.001, Ex4-Coc compared to Veh-Coc treatment). The selected dose had no significant effect on accumbal dopamine release compared to vehicle treatment at any time interval (P>0.05, Veh-Veh vs Ex4-Veh). There was a significant difference in accumbal dopamine response in vehicle treated mice and Ex4-Coc treated mice (time interval 40 minutes (P<0.05), 60 minutes (P<0.001) and 80 minutes (P<0.05)). Arrows represent time points of injection of Ex4, vehicle and cocaine. Data analyzed with a Two-way ANOVA followed by a Bonferroni post-hoc test (n=8 in each group) (C) The cocaine-induced (10 mg/kg IP) condition place preference (CPP) was attenuated by an acute single IP injection of Ex4 (2.4 µg/kg IP) in mice (n=8 in each group, *P<0.05, unpaired t-test). All values represent mean ± SEM.