The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice

Abstract

The gastrointestinal peptide glucagon-like peptide 1 (GLP-1) is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans.

Conflict of interest statement

Competing Interests: This study was financially supported by NovoNordisk. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. A coronal mouse brain section showing probe placements (illustrated by vertical lines) in the nucleus of mice used in the present study.

The number given indicates millimeters anterior (+) from bregma.

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

(A) Nicotine-induced (0.5 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 nicotine (0.5 mg/kg IP) to increase dopamine release in comparison to vehicle treatment at time intervals 40-180 minutes (**P<0.01, ***P<0.01, veh-nic compared to veh-veh treatment). Secondly we showed that pre-treatment with Ex4 (2.4 μg/kg IP) attenuated the nicotine-induced increase in dopamine release compared to vehicle pre-treatment at time interval 40-60 and 100-180 minutes (+<0.05, ++P<0.01, +++P<0.01, Ex4-nic compared to veh-nic treatment). There was no difference in response between the veh-veh and Ex4-nic groups at a dose of Ex4 that had no effect perse. Arrows represent time points of injection of Ex4, vehicle and nicotine. Data analyzed with a Two-way ANOVA followed by a Bonferroni post-hoc test (n=8 in each group) (C) The nicotine-induced (0.5 m/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. Arrow shows time for injections.

Figure 3. Exendin-4 blocks the nicotine-induced locomotor sensitization in mice.

In the present experiment nicotine or vehicle for five days. 72 hours following this sub-chronic treatment Ex4 or vehicle was administered. Sub chronic nicotine treatment induced (0.5 mg/kg) a significant sensitization and this effect was attenuated by a single injection of Ex4 (2.4 μg/kg) (n=8; * ***P<0.001, two-way ANOVA followed by a Bonferroni post-hoc test). All values represent mean ± SEM.