Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent
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Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent. / Jensen, Mathias E.; Galli, Aurelio; Thomsen, Morgane; Jensen, Kathrine L.; Thomsen, Gerda K.; Klausen, Mette K.; Vilsboll, Tina; Christensen, Mikkel B.; Holst, Jens J.; Owens, Anthony; Robertson, Sabrina; Daws, Lynette; Zanella, Daniele; Gether, Ulrik; Knudsen, Gitte M.; Fink-Jensen, Anders.
In: Neurochemistry International, Vol. 138, 104772, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - Vilsboll, 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
PY - 2020
Y1 - 2020
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 - Dopamine transporter
KW - Dopamine uptake
KW - Striatum
KW - Glucagon-like peptide-1
KW - Addiction
KW - NUCLEUS-ACCUMBENS
KW - GLP-1 ANALOG
KW - EXENDIN-4
KW - BRAIN
KW - FOOD
KW - ACTIVATION
KW - BINDING
KW - QUANTIFICATION
KW - MECHANISMS
KW - EXPRESSION
U2 - 10.1016/j.neuint.2020.104772
DO - 10.1016/j.neuint.2020.104772
M3 - Journal article
C2 - 32464226
VL - 138
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
M1 - 104772
ER -
ID: 246777178