The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice

Abstract

Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

Keywords: Addiction; Cocaine; Dopamine; Exendin-4; GLP-1; Self-administration; c-Fos.

Figure 1

(A) Basal locomotion after saline or Ex-4 treatment. Locomotion was evaluated as the total beam breaks during 90 minutes. ** p<0.01, * p<0.05. vs vehicle. (B) Cocaine-induced hyperactivity after 90 minutes of basal locomotion. Locomotor activity is presented as the total beam breaks during 90-150 minutes, * p<0.05 vs. vehicle, # p<0.05 vs. COC. (C) SKF-82,958-induced hyperactivity after 90 minutes of basal locomotion. Locomotor activity is presented as the total beam breaks during 90-150 minutes, *** p<0.0001 vs. the corresponding saline group, ## p<0.001 vs. the corresponding vehicle group.

Figure 2

(A) Pre-treatment with Ex-4 at 30 and 100μg/kg i.p. significantly decreased nose-poking for cocaine at the peak effective self-administration dose for cocaine (0.03 mg/kg/infusion). * p<0.05 vs. vehicle i.p./saline i.v.; ## p<0.01, # p<0.05 vs. vehicle i.p./cocaine i.v. (B) Dose-effect curves after acute cocaine self-administration: effects of Ex-4. Cocaine was self-administered i.v. according to an inverted U-shaped curve in NMRI mice. Pre-treatment with Ex-4 at 30μg/kg i.p. shifted cocaine's dose-effect curve downward. ** p<0.01, * p<0.05, vs. the corresponding saline i.v. group; # p<0.05 vs. the corresponding vehicle-pretreated group.

Figure 3

(A) Pre-treatment with Ex-4 at 10μg/kg i.p. significantly decreased the number of reinforcements earned following a chronic cocaine administration setup at cocaine doses of 0.03, 0,32, and 1.0 mg/kg/infusion ** p<0,01, * p<0.05 vs. vehicle i.p.but not (B) inactive responses.

Figure 4

Ex-4 attenuates cocaine-induced c-fos expression in the striatum. (A) Optical density analysis of the autoradiograms (***p<0.0001 vs. saline/saline, ###p<0.001 vs. saline/COC, Bonferonni post-hoc t-tests after significant One-way ANOVA) (B) C-fos expression in striatum determined by radioactive in situ hybridization in brain coronal slices in saline/saline group, (C) saline/COC (D) Ex-4/COC. The grey area in (B) indicates the area measured. Diagram adopted from Franklin and Paxinos [21].

Figure 5

Extracellular striatal dopamine levels in response to cocaine and Ex-4. Cocaine (30 mg/kg, s.c., black circles) significantly increased dopamine levels in mice pretreated with saline. The cocaine-induced dopamine increase was attenuated when mice were pretreated with Ex-4 (30 μg/kg, i.p., black squares). ** p<0.01, * p<0.05 vs. own basal level, Bonferroni post-hoc t-test after significant one-way ANOVA ### p<0.001, # p<0.05 vs. veh-COC, Bonferroni post-hoc t-test after significant two-way ANOVA.