GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A receptors |
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Authors: | Catarina A R V Gomes Patrícia F Simões† Paula M Canas† César Quiroz‡ Ana M Sebastião Sergi Ferré‡ Rodrigo A Cunha† Joaquim A Ribeiro |
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Institution: | Institute of Pharmacology and Neurosciences, Faculty of Medicine, and Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal; Center for Neurosciences of Coimbra, Faculty of Medicine, Institute of Biochemistry, University of Coimbra, Coimbra, Portugal; National Institute on Drug Addiction, Intramural Research Program, Department of Health and Human Services, National Institutes of Health, Baltimore, Maryland, USA |
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Abstract: | Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson's disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A2A receptor activation. As motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret ( rearranged during transfection ) and GDNF family receptor α1 controlled the cortico-striatal glutamatergic pathway in an A2A receptor-dependent manner. GDNF (10 ng/mL) enhanced (by ≈13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to ≈30%) by the A2A receptor agonist CGS 21680 (10 nM) and prevented by the A2A receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GDNF family receptor α1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A2A receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphorylation that was prevented by pre-treatment with the A2A receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A2A receptors. |
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Keywords: | A2A receptor adenosine cortico-striatal pathway glial cell line-derived neurotrophic factor glutamate rearranged during transfection/GDNF family receptor α1 |
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