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Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice.
Exp Neurol. 2014 Nov; 261:733-43.EN

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Mango D
IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Bonito-Oliva A
Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden.
Ledonne A
IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Cappellacci L
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Italy.
Petrelli R
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Italy.
Nisticò R
IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
Berretta N
IRCCS Fondazione Santa Lucia, Rome, Italy.
Fisone G
Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden.
Mercuri NB
IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address: mercurin@med.uniroma2.it.

MeSH

Action PotentialsAge FactorsAnimalsAntiparkinson AgentsCorpus StriatumDisease Models, AnimalDopamineDyskinesia, Drug-InducedEnzyme InhibitorsInhibitory Postsynaptic PotentialsLevodopaMaleMiceMice, Inbred C57BLMotor ActivityNeuronsParkinson DiseasePars ReticulataReceptor, Adenosine A1Receptors, Dopamine D1Xanthines

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25173217

Citation

Mango, Dalila, et al. "Adenosine A1 Receptor Stimulation Reduces D1 Receptor-mediated GABAergic Transmission From Striato-nigral Terminals and Attenuates l-DOPA-induced Dyskinesia in Dopamine-denervated Mice." Experimental Neurology, vol. 261, 2014, pp. 733-43.
Mango D, Bonito-Oliva A, Ledonne A, et al. Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. Exp Neurol. 2014;261:733-43.
Mango, D., Bonito-Oliva, A., Ledonne, A., Cappellacci, L., Petrelli, R., Nisticò, R., Berretta, N., Fisone, G., & Mercuri, N. B. (2014). Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. Experimental Neurology, 261, 733-43. https://doi.org/10.1016/j.expneurol.2014.08.022
Mango D, et al. Adenosine A1 Receptor Stimulation Reduces D1 Receptor-mediated GABAergic Transmission From Striato-nigral Terminals and Attenuates l-DOPA-induced Dyskinesia in Dopamine-denervated Mice. Exp Neurol. 2014;261:733-43. PubMed PMID: 25173217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. AU - Mango,Dalila, 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, Y1 - 2014/08/27/ PY - 2014/05/23/received PY - 2014/07/30/revised PY - 2014/08/02/accepted PY - 2014/9/1/entrez PY - 2014/9/1/pubmed PY - 2014/12/18/medline KW - Adenosine KW - Dopamine KW - Dyskinesia KW - GABAergic terminals KW - Levodopa KW - Mice KW - Substantia nigra pars reticulata SP - 733 EP - 43 JF - Experimental neurology JO - Exp Neurol VL - 261 N2 - 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. SN - 1090-2430 UR - https://www.unboundmedicine.com/medline/citation/25173217/Adenosine_A1_receptor_stimulation_reduces_D1_receptor_mediated_GABAergic_transmission_from_striato_nigral_terminals_and_attenuates_l_DOPA_induced_dyskinesia_in_dopamine_denervated_mice_ DB - PRIME DP - Unbound Medicine ER -