Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice

Dalila Mango, Alessandra Bonito-Oliva, Ada Ledonne, Loredana Cappellacci, Riccardo Petrelli, Robert Nisticò, Nicola Berretta, Gilberto Fisone, Nicola Biagio Mercuri

Research output: Contribution to journalArticle

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Abstract

γ-Aminobutyric acid A receptor (GABAAR)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory post-synaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs). The effect of DPCPX was also examined in a mouse model of Parkinson's disease (PD), generated by unilateral denervation of the dopaminergic input to the striatum. In this model, SKF alone was sufficient to increase sIPSCs frequency and eIPSCs amplitude, and these effects were not potentiated by DPCPX. To confirm a depressive effect of A1Rs on the synaptic release of GABA we used the selective A1R agonist 5'-chloro-5'-deoxy-N6-(±)-(endo-norborn-2-yl)adenosine (5'Cl5'd-(±)-ENBA) which has limited peripheral actions. We found that 5'Cl5'd-(±)-ENBA decreased sIPSCs frequency, without affecting their amplitude, and decreased eIPSCs amplitude. Importantly, in the PD mouse model, 5'Cl5'd-(±)-ENBA prevented the increase in sIPSC frequency and eIPSC amplitude produced by SKF. Since exaggerated DA transmission along the striato-nigral pathway is involved in the motor complications (e.g. dyskinesia) caused by prolonged and intermittent administration of l-DOPA, we examined the effect of A1R activation in mice with unilateral DA denervation. We found that 5'Cl5'd-(±)-ENBA, administered in combination with l-DOPA, reduced the development of abnormal involuntary movements. These results indicate the potential benefit of A1R agonists for the treatment of l-DOPA-induced dyskinesia and hyperkinetic disorders providing a mechanistic framework for the study of the interaction between DA and adenosine in the striatonigral system.

Original languageEnglish
Pages (from-to)733-743
Number of pages11
JournalExperimental Neurology
Volume261
DOIs
Publication statusPublished - Nov 1 2014

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Adenosine A1 Receptors
Dyskinesias
Substantia Nigra
Dopamine
Denervation
Adenosine
Parkinson Disease
Adenosine A1 Receptor Antagonists
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Aminobutyrates
Dopamine D1 Receptors
Synaptic Potentials
Papaverine
Phosphodiesterase Inhibitors
Dopamine Agonists
gamma-Aminobutyric Acid
1,3-dipropyl-8-cyclopentylxanthine
Neurons
Brain

Keywords

  • Adenosine
  • Dopamine
  • Dyskinesia
  • GABAergic terminals
  • Levodopa
  • Mice
  • Substantia nigra pars reticulata

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Medicine(all)

Cite this

Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. / Mango, Dalila; Bonito-Oliva, Alessandra; Ledonne, Ada; Cappellacci, Loredana; Petrelli, Riccardo; Nisticò, Robert; Berretta, Nicola; Fisone, Gilberto; Mercuri, Nicola Biagio.

In: Experimental Neurology, Vol. 261, 01.11.2014, p. 733-743.

Research output: Contribution to journalArticle

Mango, Dalila ; Bonito-Oliva, Alessandra ; Ledonne, Ada ; Cappellacci, Loredana ; Petrelli, Riccardo ; Nisticò, Robert ; Berretta, Nicola ; Fisone, Gilberto ; Mercuri, Nicola Biagio. / Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. In: Experimental Neurology. 2014 ; Vol. 261. pp. 733-743.
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AU - Bonito-Oliva, Alessandra

AU - Ledonne, Ada

AU - Cappellacci, Loredana

AU - Petrelli, Riccardo

AU - Nisticò, Robert

AU - Berretta, Nicola

AU - Fisone, Gilberto

AU - Mercuri, Nicola Biagio

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KW - Levodopa

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