The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice
Introduction
Drug abuse and drug dependence are major health problems, and effective pharmacological interventions to treat them are lacking. To develop novel treatment strategies, a better understanding of the complex neurobiology involved in drug abuse and drug dependence is needed. Midbrain dopaminergic neurons projecting to the nucleus accumbens (NAc) are believed to mediate the reinforcing effects of drugs of abuse [1], [2], which play a pivotal role in the development of drug abuse and drug dependence. Therefore, research efforts have focused on the development of candidates that interact with the dopamine reward system.
Glucagon-like peptide 1 (GLP-1) is a peptide produced in enteroendocrine L-cells of the intestinal mucosa [3] and secreted from the intestinal tract in response to food intake [4]. However, GLP-1 is also localized in the neurons of the brainstem nucleus of the solitary tract (NTS), which has widespread projections within the central nervous system (CNS) [5]. GLP-1 receptors are expressed in the ventral tegmental area (VTA) and NAc [6] and it has recently been shown that GLP-1-producing NTS neurons project directly to the VTA and the shell and core regions of the NAc [7].
Selective GLP-1 receptor agonists, e.g., liraglutide (Victoza©) and exenatide (Byetta©), increase insulin secretion, decrease glucagon secretion and gastric emptying and are used in the clinic to treat type 2 diabetes [8]. GLP-1 is also known to reduce food intake and body weight in rodents, most likely mediated via a central effect [9], [10], and similar effects have also been reported in humans [11].
Exendin-4 (Ex-4) is a selective GLP-1 agonist. The native hormone is produced in the gut of the Gila monster Heloderma suspectum, a desert reptile, and found at a high concentration in its saliva. Ex-4 is able to cross the blood–brain barrier [12], [13] and has been shown to regulate food reward in rats by a central mode of action [14]. Emerging data suggest that GLP-1 receptor signaling may modulate hedonic behaviors [15]. For instance, Ex-4 attenuates d-amphetamine-induced hyperactivity [16] as well as cocaine-induced place preference [17] and self-administration of alcohol in mice [18].
Considering the anatomical and functional relationship between GLP-1 receptors and the brain reward system, we decided to further investigate whether GLP-1 receptor stimulation modulates the addictive properties of the indirect dopamine receptor agonist cocaine. To this end, we studied the effects of Ex-4 on acute and chronic cocaine self-administration and show for the first time, that Ex-4 attenuates these effects. In addition we show that Ex-4 can inhibit dopamine D1 receptor- and cocaine-induced hyperlocomotion as well as cocaine-induced striatal dopamine release and striatal c-fos expression in mice.
Section snippets
Animals
Male NMRI mice (Taconic, Denmark) that weighed 28–35 g were used for microdialysis and locomotor activity experiments, male NMRI mice that weighed 20–22 g were used for the acute self-administration experiment and male C57Bl/6 mice weighing 20–24 g were used for chronic self-administration experiments. All mice were housed in Makrolon cages (20 × 35 × 15 cm) enriched with cardboard housing and nesting material. The animals were kept at room temperature (22°C ± 2) in a 12-hour light/dark cycle (lights on
Exendin-4 inhibits basal and cocaine-induced locomotor activity
First, we measured cocaine-induced hyperactivity, as total beam breaks during the time interval 90–150 min, in the vehicle/COC group. This observed increase in cocaine-induced activity was attenuated in the groups pretreated with Ex-4 at doses of 3 and 30 μg/kg, but not at 0.3 μg/kg, although this dose appeared marginally effective as well (one-way ANOVA, F(4,49) = 3.65; p < 0.05, nvehicle/vehicle = 13, nvehicle/COC = 14, nEx-4/COC = 8–10, Fig. 1B). We also measured basal locomotion as total beam breaks
Discussion
In the present study, we report for the first time that stimulation of the GLP-1 receptor causes a marked reduction in acute and chronic cocaine self-administration. The GLP-1 analogue Ex-4 used in this study crosses the blood–brain barrier [12], [13]. Furthermore, our striatal microdialysis and c-fos data strongly indicate that the observed effects of Ex-4 on cocaine reward are centrally mediated. In accordance with this, it is well known that GLP-1 receptors are expressed in the brain [5],
Acknowledgments
The Ivan Nielsen Foundation, the Novo Nordisk Foundation R179-A15612 and the Lundbeck Foundation R108-A11052 supported the present work. This work was also supported by National Institutes of Health Grant DA035588 to A.G. and G.D.S. and DA036940 to I.A.R., as well as a Public Health Service Award T32 GM07347 from the National Institute of General Medical Studies. We thank Birgit Hansen for expert technical assistance.
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2022, Brain Research BulletinCitation Excerpt :The present data add to a now growing literature suggesting that GLP-1RAs show promise as a new treatment for substance use disorders. As alluded to, a large number of reports suggest that GLP-1RAs may be useful in the treatment of other SUDs, (Egecioglu et al., 2013a, 2013b; Sorensen et al., 2015; Schmidt et al., 2016; Graham et al., 2013; Hernandez et al., 2018) while our lab and others have provided evidence that GLP-1RAs also are effective in animal models of OUD (Douton et al., 2021, 2022a,b, Zhang et al., 2020, 2021). In the present paper we found that titrating the dose to 0.3 mg/kg liraglutide was most effective in reducing heroin-seeking behaviors, particularly in rats with a history of high heroin self-administration.