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.

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

“…The ability of the GLP-1 system to modulate dopamine signaling, likely underlying reward-driven behavioral alterations, is supported by studies employing microdialysis. Using this technique, which samples fluctuations in extracellular dopamine over minutes, studies have shown suppression of cocaine-induced increases in NAc dopamine concentration by Exendin-4 [35,39]. Our data suggest that this suppression is limited to the NAc core (Figures 3 and 4) and that terminal mechanisms for shaping extracellular dopamine concentration (e.g.…”

“…Previous work demonstrating suppression of dopamine by Exendin-4 used systemic injection [35,39] which would target both peripheral and central GLP-1Rs, as Exendin-4 does cross the blood brain barrier [90]. While our data suggest a central site of action, the central population of GLP-1Rs that are targeted to exert effects on dopamine signaling remains unknown.…”

“…With respect to cocaine, Exendin-4 decreases cocaine-induced locomotion, conditioned place preference and self-administration [35–37,39]. GLP-1R agonism also suppresses hyperactivity induced by the non-selective dopamine agonist apomorphine [84].…”

“…Intra-VTA or NAc infusion of the GLP-1R agonist, Exendin-4, reduces palatable food intake [32,33] and goal-directed behavior for food [31]. Interestingly GLP-1R agonists also suppress goal-directed behavior for cocaine reward [35–39], likely by attenuating dopamine signaling in the NAc [35,39]. However, suppression of cocaine-evoked NAc dopamine release was demonstrated utilizing microdialysis, which lacks the spatiotemporal resolution to allow for investigation of phasic dopamine release patterns as well as potential regional differences.…”

Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses

“…Furthermore, the presence of or even the expectancy of cocaine depresses leptin concentrations, while leptin administration inhibits cocaine-induced seeking behavior and reward (You et al, 2016). The administration of the GLP-1 analog exendin-4 to rodents reduces the rewarding effects of cocaine, cocaine self-administration and cocaine-induced CPP (Egecioglu et al, 2013; Graham et al, 2013; Reddy et al, 2016; Schmidt et al, 2016; Sørensen et al, 2015). In contrast, insulin enhances the function of cocaine-sensitive dopamine and norepinephrine transporters in the rat NAc by acting at the presynaptic level (Schoffelmeer et al, 2011).…”