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

Mathias E. Jensen, Aurelio Galli, Morgane Thomsen, Kathrine L. Jensen, Gerda K. Thomsen, Mette K. Klausen, Tina Vilsbøll, Mikkel B. Christensen, Jens J. Holst, Anthony Owens, Sabrina Robertson, Lynette Daws, Daniele Zanella, Ulrik Gether, Gitte M. Knudsen, Anders Fink-Jensen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number104772
JournalNeurochemistry International
Volume138
DOIs
StatePublished - Sep 2020

Keywords

  • Addiction
  • Dopamine transporter
  • Dopamine uptake
  • Glucagon-like peptide-1
  • Striatum

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Fingerprint Dive into the research topics of 'Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent'. Together they form a unique fingerprint.

  • Cite this

    Jensen, M. E., Galli, A., Thomsen, M., Jensen, K. L., Thomsen, G. K., Klausen, M. K., Vilsbøll, T., Christensen, M. B., Holst, J. J., Owens, A., Robertson, S., Daws, L., Zanella, D., Gether, U., Knudsen, G. M., & Fink-Jensen, A. (2020). Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent. Neurochemistry International, 138, [104772]. https://doi.org/10.1016/j.neuint.2020.104772