GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A₂A receptors

• Published in: Journal of neurochemistry 2009-03, Vol.108 (5), p.1208-1219
• Main Authors: Gomes, Catarina A.R.V, Simões, Patrícia F, Canas, Paula M, Quiroz, César, Sebastião, Ana M, Ferré, Sergi, Cunha, Rodrigo A, Ribeiro, Joaquim A
• Format: Article
• Language: English
• Subjects: A2A receptor; Adenosine; A₂A receptor; Biochemistry; Biological and medical sciences; cortico-striatal pathway; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; glial cell line-derived neurotrophic factor; glutamate; Medical sciences; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurotransmitters; Parkinson's disease; rearranged during transfection/GDNF family receptor α1
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.05876.x

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 [almost equal to]13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to [almost equal 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.