1. Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent.
- Author
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Jensen ME, Galli A, Thomsen M, Jensen KL, Thomsen GK, Klausen MK, Vilsbøll T, Christensen MB, Holst JJ, Owens A, Robertson S, Daws L, Zanella D, Gether U, Knudsen GM, and Fink-Jensen A
- Subjects
- Adolescent, Adult, Animals, Corpus Striatum drug effects, Dopamine Antagonists pharmacology, Dopamine Plasma Membrane Transport Proteins antagonists & inhibitors, Dopamine Plasma Membrane Transport Proteins genetics, Exenatide pharmacology, Female, Glucagon-Like Peptide 1 antagonists & inhibitors, Glucagon-Like Peptide 1 genetics, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Organ Culture Techniques, Peptide Fragments antagonists & inhibitors, Peptide Fragments genetics, Rats, Rats, Sprague-Dawley, Species Specificity, Tomography, Emission-Computed, Single-Photon methods, Young Adult, Corpus Striatum metabolism, Dopamine metabolism, Dopamine Plasma Membrane Transport Proteins metabolism, Glucagon-Like Peptide 1 metabolism, Peptide Fragments metabolism
- 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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