Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent.,Neurochemistry international

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Glucagon-like peptide-1 receptor regulation of basal dopamine transporter activity is species-dependent.
Neurochemistry international ( IF 4.2 ) Pub Date : 2020-05-25 , DOI: 10.1016/j.neuint.2020.104772
Mathias E Jensen ₁ , Aurelio Galli ₂ , Morgane Thomsen ₁ , Kathrine L Jensen ₃ , Gerda K Thomsen ₄ , Mette K Klausen ₁ , Tina Vilsbøll ₅ , Mikkel B Christensen ₆ , Jens J Holst ₇ , Anthony Owens ₈ , Sabrina Robertson ₉ , Lynette Daws ₈ , Daniele Zanella ₂ , Ulrik Gether ₃ , Gitte M Knudsen ₁₀ , Anders Fink-Jensen ₁₁

Affiliation

Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Denmark.
Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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; Steno Diabetes Center Copenhagen, Gentofte Hospital, Denmark.
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.
Novo Nordisk Foundation Center for Basic Metabolic Research Endocrinology and Metabolism, Copenhagen, Denmark.
Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, USA.
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, USA.
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.
Psychiatric Centre Copenhagen, University Hospital of Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.

中文翻译：

胰高血糖素样肽-1 受体对基础多巴胺转运蛋白活性的调节是物种依赖性的。

介绍

大量临床前证据表明，胰高血糖素样肽-1 受体 (GLP-1R) 激动剂可减弱物质使用障碍相关行为的影响。这些影响背后的机制仍然难以捉摸。在本研究中，我们假设 GLP-1R 激活调节多巴胺转运蛋白 (DAT)，从而调节纹状体中的多巴胺 (DA) 稳态。这在三个不同的实验中进行了评估：两个临床前实验和一个临床实验。

方法

在体外 GLP-1 (7-36)-酰胺暴露后评估大鼠纹状体 DA 摄取、DA 清除和 DAT 细胞表面表达。在用 GLP-1R 激动剂艾塞那肽全身治疗后，离体评估小鼠的 DA 摄取。此外，在 GLP-1R 敲除小鼠中测量了 DA 摄取，并与野生型小鼠中的 DA 摄取进行了比较。在健康人中，通过单光子发射计算机断层扫描成像测量的艾塞那肽输注过程中评估了 DAT 可用性的变化。