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

doi:10.1016/j.brainres.2006.07.025

Brain Research

Volume 1113, Issue 1, 3 October 2006, Pages 129-136

https://doi.org/10.1016/j.brainres.2006.07.025 Get rights and content

Abstract

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 (S₁ and S₂); GDNF was added before S₂ and drugs used to modify GDNF actions were present during both stimulation periods. The effect of GDNF was taken as the change in the S₂/S₁ 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.

Introduction

Glial cell line-derived neurotrophic factor (GDNF) was originally identified as a potent trophic factor for cultured midbrain dopaminergic neurons and exerts an essential role in the development and maintenance of those neurons (Lin et al., 1993). In rodent and primate models of Parkinson's disease involving selective degeneration of dopaminergic neurons, GDNF has been shown to be neuroprotective, to promote fiber outgrowth and to improve motor function when delivered into the cerebral ventricles or directly into the striatum or substantia nigra (Björklund et al., 1997, Gash et al., 1996, Tomac et al., 1995). Results obtained either in an open clinical trial with intraputamenal infusion of GDNF (Patel et al., 2005) as well as with postmortem analysis of a patient of the same clinical trial (Love et al., 2005) pointed out towards a therapeutic potential of GDNF in Parkinson's disease. However, an intense debate of the therapeutical potential of GDNF in this neurodegenerative disease (Barker, 2006, Kotzbauer and Holtzman, 2006) started recently due to the negative outcome of a double blind randomized clinical trial also with GDNF infusion in the putamen (Lang et al., 2006). This controversy clearly pointed out the need of further laboratory studies to clarify GDNF actions on dopaminergic neurons.

Evidence has been accumulating that supports a facilitatory role for GDNF in striatal dopamine release in vivo (Grondin et al., 2003, Hebert and Gerhardt, 1997, Smith et al., 2005). This neurotrophic factor also exerts an acute effect on the function of midbrain dopaminergic neurons in culture, rapidly and reversibly inhibiting A-type potassium channels, leading to an increase of their excitability (Yang et al., 2001). These GDNF actions can secondarily cause an increase in dopamine release in the striatum, but a direct evaluation of GDNF actions on isolated dopaminergic nerve endings has not yet been reported so far.

On the other hand, it is well established that adenosine A_2A receptors modulate striatal function. A_2A receptors are highly expressed in the striatum, predominantly in the medium spiny striatopallidal output neurons (see Svenningsson et al., 1999). Though A_2A receptors do not directly influence dopamine release at striatal slices (Jin et al., 1993, Lupica et al., 1990), these receptors modulate the release of other neurotransmitters from striatal nerve endings, namely GABA and acetylcholine (Kirk and Richardson, 1994) as well as glutamate (Rodrigues et al., 2005).

It, therefore, seemed of interest to evaluate if GDNF could presynaptically modulate dopamine release and if so, whether adenosine A_2A receptors could modulate that action of GDNF. So, we chose purified nerve terminals or synaptosomes as experimental model to study presynaptic phenomena, since they enable the direct evaluation of nerve terminal function (Raiteri and Raiteri, 2000). As slices retain local anatomical integrity, they allow additional modulation of [³H]dopamine release; so, it was also considered important to evaluate the effect of GDNF in this preparation, where anatomical connections are more preserved.

Section snippets

GDNF enhances dopamine release from striatal isolated nerve endings

In striatal synaptosomes incubated with [³H]dopamine, the initial (first three collected samples) basal release of tritium was 1.73 ± 0.02% of the total tritium incorporated in the synaptosomes (fractional release) (n = 12). The first stimulation period (S₁) caused a twofold increase in the amount of tritium release, whereas the second caused a smaller increase, so that the S₂/S₁ ratio obtained was 0.56 ± 0.02 (n = 12). When GDNF (10 ng/ml) was present during S₂, the S₂/S₁ ratio was increased to 0.80 ±

Discussion

The main findings in the present work are that (a) GDNF acutely increases evoked dopamine release in rat striatal slices and synaptosomes; (b) the GDNF-induced enhancement of dopamine release is modulated by adenosine A_2A receptors, which provides a first evidence for a crosstalk between adenosine A_2A receptors and GDNF in the striatum.

Intranigral injections of GDNF (Hebert and Gerhardt, 1997) or of an adenoviral vector encoding for GDNF (Smith et al., 2005) enhance striatal dopamine levels and

Preparation of striatal synaptosomes and slices

The experiments were performed on striatal preparations from male Wistar rats (3–4 weeks old) from Harlam Interfauna Iberica, SL (Barcelona). The animals were handled according to European Community guidelines and Portuguese law on Animal Care and anesthetized with halothane before decapitation. The striatum was dissected free within ice-cold Krebs solution containing pargyline (10 μM), composed of (mM): NaCl 124; KCl 3; NaH₂PO₄ 1.25; NaHCO₃ 26; MgSO₄ 1; CaCl₂ 2; and glucose 10, previously

Acknowledgments

Catarina A.R.V. Gomes is in receipt of an FCT PhD fellowship (SFRH/BD/13553/2003-POCTI). Sandra H. Vaz is an receipt of an FCT Studentship. This work was supported by FCT.

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

Abstract

Introduction

Section snippets

GDNF enhances dopamine release from striatal isolated nerve endings

Discussion

Preparation of striatal synaptosomes and slices

Acknowledgments

Lancet

Neurobiol. Dis.

Neuropharmacology

Trends Neurosci.

Neurochem. Int.

Trends Pharmacol. Sci.

Exp. Neurol.

Prog. Neurobiol.

Neuropharmacology

Neuroscience

Neuroprotection induced by adenosine A2A antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways

Exp. Brain Res.

Translating A2A antagonist KW6002 from animal models to Parkinsonian patients

Neurology

Glutamate mGlu5-adenosine A2A-dopamine D2 receptor interactions in the striatum. Implications for drug therapy in neuro-psychiatric disorders and drug abuse

Curr. Med. Chem.

Functional recovery in parkinsonian monkeys treated with GDNF

Nature

Glial cell line-derived neurotrophic factor increases stimulus-evoked dopamine release and motor speed in aged rhesus monkeys

J. Neurosci.

Behavioral and neurochemical effects of intranigral administration of glial cell line-derived neurotrophic factor on aged Fischer 344 rats

J. Pharmacol. Exp. Ther.

Research Report
Glial cell line-derived neurotrophic factor (GDNF) enhances dopamine release from striatal nerve endings in an adenosine A_2A receptor-dependent manner

Translating A_2A antagonist KW6002 from animal models to Parkinsonian patients

Glutamate mGlu5-adenosine A_2A-dopamine D2 receptor interactions in the striatum. Implications for drug therapy in neuro-psychiatric disorders and drug abuse