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

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 A(2A) 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 alpha1 controlled the cortico-striatal glutamatergic pathway in an A(2A) receptor-dependent manner. GDNF (10 ng/mL) enhanced (by approximately 13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to approximately 30%) by the A(2A) receptor agonist CGS 21680 (10 nM) and prevented by the A(2A) receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GDNF family receptor alpha1 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 A(2A) 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 A(2A) 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 A(2A) receptors.

Glial cell line-derived neurotrophic factor (GDNF) enhances dopamine release from striatal nerve endings in an adenosine A2A receptor-dependent manner.

Both glial cell line-derived neurotrophic factor (GDNF) and adenosine influence dopaminergic function in the striatum. We now evaluated the GDNF effect on dopamine release from rat striatal nerve endings and if this effect of GDNF is modulated by adenosine A(2A) receptors. Dopamine release was evoked twice (S(1) and S(2)); GDNF was added before S(2) and drugs used to modify GDNF actions were present during both stimulation periods. The effect of GDNF was taken as the change in the S(2)/S(1) ratio in the absence and in the presence of GDNF in the same experimental conditions. GDNF (3-30 ng/ml) increased dopamine release from K(+) (20 mM, 2 min) stimulated synaptosomes and electrically (2 Hz, 2 min) stimulated striatal slices, an effect dependent upon tonic adenosine A(2A) receptor activation, since it was blocked by the A(2A) receptor antagonist, SCH 58261 (50 nM). Activation of A(2A) receptors with CGS 21680 (10 nM) potentiated the effect of GDNF in synaptosomes. CGS 21680 also potentiated the effect of GDNF in striatal slices, providing that GABAergic transmission was inhibited; if not, the action of GDNF was attenuated by CGS 21680. Blockade of GABAergic transmission per se increased dopamine release, but attenuated the effect of GDNF upon dopamine release in slices. The results suggest that GDNF enhances dopamine release by acting presynaptically at the striatum, an action that requires adenosine A(2A) receptor activity. Furthermore, in striatal slices, the action of GDNF as well as its modulation by adenosine A(2A) receptor activation appears to be also under control of GABAergic transmission.