TY - JOUR

T1 - Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent

AU - Jensen, Mathias E

AU - Galli, Aurelio

AU - Thomsen, Morgane

AU - Jensen, Kathrine L

AU - Thomsen, Gerda K

AU - Klausen, Mette K

AU - Vilsbøll, Tina

AU - Christensen, Mikkel B

AU - Holst, Jens J

AU - Owens, Anthony

AU - Robertson, Sabrina

AU - Daws, Lynette

AU - Zanella, Daniele

AU - Gether, Ulrik

AU - Knudsen, Gitte M

AU - Fink-Jensen, Anders

N1 - Copyright © 2020 Elsevier Ltd. All rights reserved.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - Addiction

KW - Dopamine transporter

KW - Dopamine uptake

KW - Glucagon-like peptide-1

KW - Striatum

UR - http://www.scopus.com/inward/record.url?scp=85086715729&partnerID=8YFLogxK

U2 - 10.1016/j.neuint.2020.104772

DO - 10.1016/j.neuint.2020.104772

M3 - Journal article

C2 - 32464226

VL - 138

SP - 104772

JO - Neurochemistry International

JF - Neurochemistry International

SN - 0197-0186

M1 - 104772

ER -