title: Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice.
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-N(6)-(±)-(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.
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Dalila
authors.initials: D
authors.lastname: Mango
authors.affiliation: Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonito-Oliva
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Ledonne
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Berretta
authors.affiliation: Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address: mercurin@med.uniroma2.it.
authors.forename: Nicola Biagio
authors.initials: NB
authors.lastname: Mercuri
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D065841:Pars Reticulata / Q000166:cytology / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; D017447:Receptors, Dopamine D1; D014970:Xanthines; D007980:Levodopa; C051360:1,3-dipropyl-8-cyclopentylxanthine; D004298:Dopamine
keywords: Adenosine; Dopamine; Dyskinesia; GABAergic terminals; Levodopa; Mice; Substantia nigra pars reticulata