Mathias E Jensen1, Aurelio Galli2, Morgane Thomsen3, Kathrine L Jensen4, Gerda K Thomsen5, Mette K Klausen3, Tina Vilsbøll6, Mikkel B Christensen7, Jens J Holst8, Anthony Owens9, Sabrina Robertson10, Lynette Daws9, Daniele Zanella2, Ulrik Gether4, Gitte M Knudsen11, Anders Fink-Jensen12. 1. Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Denmark. Electronic address: mathias.ebbesen.jensen.01@regionh.dk. 2. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA. 3. Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Denmark. 4. Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Neurobiology Research Unit, Neuroscience Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 6. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte Hospital, Denmark. 7. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Denmark. 8. Novo Nordisk Foundation Center for Basic Metabolic Research Endocrinology and Metabolism, Copenhagen, Denmark. 9. Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, USA. 10. Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, USA. 11. Neurobiology Research Unit, Neuroscience Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 12. Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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: 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.
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