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Glutamatergic mechanisms in l-DOPA-induced dyskinesia and therapeutic implications

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Overactivation of the glutamatergic synapse leading to maladaptive synaptic plasticity in the basal ganglia is a well-demonstrated process involved in the onset of l-DOPA-induced dyskinesia (LID). Changes in glutamate release are paralleled by compensatory modifications of the expression and/or synaptic localization of both ionotropic and metabotropic glutamate receptors (mGluRs). Accordingly, compounds targeting N-methyl-d-aspartate glutamate receptors (NMDARs) and specific subtypes of metabotropic glutamate receptors (mGluR4 and mGluR5) have been tested both in preclinical and clinical studies. At present, amantadine, a low-affinity non-competitive NMDAR antagonist, represents the only recommended add-on agent with a moderate anti-dyskinetic activity. The present review describes recent advances in basic research, preclinical and early clinical studies in the attempt of identifying innovative strategies for an accurate modulation of both pre- and postsynaptic glutamate receptors to reduce the severity of LID. Even if a complete understanding of LID molecular bases is still lacking, several compounds demonstrated an anti-dyskinetic activity in preclinical and early clinical studies. These results indicate that modulation of the glutamatergic system remains one of the most promising pharmacological strategies in the field.

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Funding

This work was supported by Umberto Veronesi Foundation Post-doctoral fellowship—Grant 2015 to MM and Progetto di Ricerca di Interesse Nazionale (PRIN2015FNWP34) to FG.

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  1. Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, 20133, Milan, Italy

    Manuela Mellone & Fabrizio Gardoni

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  1. Manuela Mellone
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  2. Fabrizio Gardoni
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Correspondence to Fabrizio Gardoni.

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Mellone, M., Gardoni, F. Glutamatergic mechanisms in l-DOPA-induced dyskinesia and therapeutic implications. J Neural Transm 125, 1225–1236 (2018). https://doi.org/10.1007/s00702-018-1846-8

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