Rebalance of striatal NMDA/AMPA receptor ratio underlies the reduced emergence of dyskinesia during D2-like dopamine agonist treatment in experimental Parkinson's disease

Vincenza Bagetta, Carmelo Sgobio, Valentina Pendolino, Giulia Del Papa, Alessandro Tozzi, Veronica Ghiglieri, Carmela Giampa', Elisa Zianni, Fabrizio Gardoni, Paolo Calabresi, Barbara Picconi

Research output: Contribution to journalArticle

Abstract

Dopamine replacement with levodopa (L-DOPA) represents the mainstay of Parkinson’s disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as L-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem inPDtreatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to L-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with L-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.
Original languageEnglish
Pages (from-to)17921-17931
Number of pages11
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume32
DOIs
Publication statusPublished - 2012

Keywords

  • Animals
  • Benzothiazoles
  • Corpus Striatum
  • Dopamine Agonists
  • Dose-Response Relationship, Drug
  • Dyskinesia, Drug-Induced
  • Excitatory Postsynaptic Potentials
  • Levodopa
  • Male
  • Neurons
  • Oxidopamine
  • Parkinsonian Disorders
  • Rats
  • Rats, Wistar
  • Receptors, AMPA
  • Receptors, Dopamine D3
  • Receptors, N-Methyl-D-Aspartate

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