Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent

Highlights

• GLP-1 (7–36)-amide increased DA uptake, DAT expression and DA clearance in rats.

• No effect of exenatide on DA uptake and no change in DA uptake in GLP-1R KO in mice.

• No acute effect of exenatide on DAT availability in striatum in healthy individuals.

Abstract

Introduction

A solid body of preclinical evidence shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the effects of substance use disorder related behaviors. The mechanisms underlying these effects remain elusive. In the present study, we hypothesized that GLP-1R activation modulates dopaminetransporter (DAT) and thus dopamine (DA) homeostasis in striatum. This was evaluated in three different experiments: two preclinical and one clinical.

Methods

Rat striatal DA uptake, DA clearance and DAT cell surface expression was assessed following GLP-1 (7-36)-amide exposure in vitro. DA uptake in mice was assesed ex vivo following systemic treatment with the GLP-1R agonist exenatide. In addition, DA uptake was measured in GLP-1R knockout mice and compared with DA-uptake in wild type mice. In healthy humans, changes in DAT availability was assessed during infusion of exenatide measured by single-photon emission computed tomography imaging.

Results

In rats, GLP-1 (7-36)-amide increased DA uptake, DA clearance and DAT cell surface expression in striatum. In mice, exenatide did not change striatal DA uptake. In GLP-1R knockout mice, DA uptake was similar to what was measured in wildtype mice. In humans, systemic infusion of exenatide did not result in acute changes in striatal DAT availability.

Conclusions

The GLP-1R agonist-induced modulation of striatal DAT activity in vitro in rats could not be replicated ex vivo in mice and in vivo in humans. Therefore, the underlying mechanisms of action for the GLP-1R agonists-induced efficacy in varios addiction-like behavioural models still remain.

Introduction

Natural reward and drug reward converge on a common neural pathway, the mesolimbic dopamine system. Since drugs activate the same reward system that underlies food reward (Volkow et al., 2013) it is perhaps no surprise that appetite-regulating peptides, besides governing energy homeostasis, also target brain areas associated with reward and addiction (Engel and Jerlhag, 2014). Glucagon-like peptide-1 (GLP-1) is a peptide that acts both as an incretin hormone that regulates blood sugar and as a neuropeptide in the brain regulating satiety (Holst, 2013). Its anorexic and glucoregulatory effects are well-established and GLP-1 receptor (GLP-1R) agonists (GLP-1RA) are approved for clinical use in type 2 diabetes and obesity (Isaacs et al., 2016). Recent years of research have broadened the understanding of the GLP-1 system especially by linking it to the rewarding properties of food (Dickson et al., 2012; Skibicka, 2013; Sisley et al., 2014). In the brain, GLP-1Rs are found in areas associated with reward, reinforcement and addiction including the ventral tegmental area (VTA) and striatum (Göke et al., 1995; Merchenthaler et al., 1999; Alhadeff et al., 2012). The VTA and its dopaminergic projections to the nucleus accumbens (NAc) orchestrate motivated behavior to obtain natural reward (such as food and sex) but are prone to be hijacked by artificial reward substances (such as drugs of abuse and alcohol) ultimately leading to addiction (Koob, 1992). Importantly, many appetite-regulating hormones including GLP-1 exert a direct influence on the VTA and NAc (Fulton, 2010). Taken together these data have led to the hypothesis that the central GLP-1R system modulates the reward system. Indeed, systemic or central administration of GLP-1RAs in rodents and non-human primates attenuate addiction-related effects of alcohol, central stimulants and nicotine (Graham et al., 2013; Egecioglu et al., 2013; Sørensen et al., 2015; Reddy et al., 2016; Fortin and Roitman, 2017; Thomsen et al., 2017, 2019; Brunchmann et al., 2019, Tuesta et al., 2017). In addition, gene variants of GLP-1R in humans have been associated with the prevalence of alcohol use disorder (AUD) (Suchankova et al., 2015).

Although GLP-1R activation attenuates the rewarding properties of food, drugs and alcohol, the underlying mechanisms remain largely unknown. We recently suggested a link between GLP-1R activation and the dopamine transporter (DAT) that regulates dopamine (DA) homeostasis in the lateral septum (LS) of the brain (Reddy et al., 2016), and elsewhere. GLP-1Rs are highly expressed in LS, which is also associated with reward (OLDS and MILNER, 1954). Brain DA plays a pivotal role in drug addiction and since plasma membrane DAT is essential for terminating DA neurotransmission, regulation of DAT may or may not underlie the observed effects of GLP-1R on reward. Since the striatum serves as a central interface in the reward system (Yager et al., 2015) we wanted to investigate if the GLP-1R system modulates DAT and consequently, levels of synaptic DA.

Here we report data using native GLP-1 (rodents) and GLP-1RA (humans) as tools in three different studies; two studies in rodents and one study in healthy humans. Our hypothesis was supported by the present rat striatal data, but not by data from mice or humans.