Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease
Open accessAbstract
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 in PD treatment. 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/AMPA receptor ratio and the AMPA receptor 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.
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The NMDA/AMPA current ratio provides a measure of NMDAR activity relative to AMPAR activity, regardless of the number of presynaptic afferents recruited and stimulating electrode positioning.
“The NMDA/AMPA current ratio provides a measure of NMDAR activity relative to AMPAR activity, regardless of the number of presynaptic afferents recruited and stimulating electrode positioning34.”
From Transient blockade of ERK phosphorylation in the critical period causes autistic phenotypes as an adult in mice (2015) · cites this paper as [34]
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- Authors
- Bagetta, V., Sgobio, C., Pendolino, V., Del Papa, G., Tozzi, A., Ghiglieri, V., Giampà, C., Zianni, E., Gardoni, F., Calabresi, P., & Picconi, B.
- Affiliations
- Fondazione Santa Lucia (IT)
- University of Perugia (IT)
- University of Milan (IT)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-12-05
- Volume
- 32
- Issue
- 49
- Pages
- 17921-17931
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6621675
- OpenAlex
- W2069463443
- Cited by
- 74
- References
- 62
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 1 · 2018: 6 · 2017: 8 · 2016: 6 · 2015: 9 · 2014: 11 · 2013: 4
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- Funders
- Sanofi
- Biogen
- European Commission (222918)
- Fondazione Cariplo (2010-0661, project number 2010-0661)
- Ministero della Salute
- Eisai
- H. Lundbeck A/S
- UCB Pharma
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- Parkinson's disease, levodopa-induced dyskinesia, pramipexole, striatum, AMPA receptor subunit composition, synaptic plasticity, experimental parkinsonism, levodopa, motor complications
- MeSH terms
- Pramipexole, Animals, Corpus Striatum, Dose-Response Relationship, Drug, Dyskinesia, Drug-Induced, Levodopa, Male, Neurons, Receptors, N-Methyl-D-Aspartate, Oxidopamine, Rats, Wistar, Receptors, AMPA, Dopamine Agonists, Excitatory Postsynaptic Potentials, Parkinsonian Disorders, Receptors, Dopamine D3, Rats, Benzothiazoles
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