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Eltoprazine prevents levodopa‐induced dyskinesias by reducing striatal glutamate and direct pathway activity
Author(s) -
Paolone Giovanna,
Brugnoli Alberto,
Arcuri Ludovico,
Mercatelli Daniela,
Morari Michele
Publication year - 2015
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.26326
Subject(s) - levodopa , glutamate receptor , pharmacology , neuroscience , medicine , psychology , parkinson's disease , receptor , disease
Background Preclinical and clinical evidence that the serotonergic system plays a major role in levodopa‐induced dyskinesias has been provided. Selective serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT 1A or 5‐HT 1B receptor agonists, and, very recently, the mixed 5‐HT 1A /5‐HT 1B receptor agonist, eltoprazine, proved effective in inhibiting l ‐dopa‐induced dyskinesias in experimental animals and parkinsonian patients. Here, we investigate the mechanisms underlying this effect. Methods Microdialysis was employed in 6‐hydroxydopamine‐hemilesioned rats chronically treated with l ‐dopa alone or in combination with eltoprazine. Gamma‐aminobutyric acid (GABA) and glutamate levels were monitored on l ‐dopa in the dopamine‐depleted striatum and ipsilateral SNr. Motor activity on the rotarod was assessed, both off and on l ‐dopa. Western blot was used to quantify ex vivo striatal levels of phosphorylated extracellular signal‐regulated kinase 1 and 2. Striatal and nigral amino acid levels, as well as striatal dopamine levels, were also monitored in l ‐dopa‐primed dyskinetic rats acutely challenged with l ‐dopa and eltoprazine. Results Eltoprazine attenuated the development and expression of dyskinesias, preserving motor coordination on the rotarod. Eltoprazine prevented the rise of nigral amino acids and striatal glutamate levels, as well as the increase in striatal phosphorylated extracellular signal‐regulated kinase 1 and 2, associated with dyskinesias. However, eltoprazine did not affect the l ‐dopa‐induced increase in striatal dopamine. Conclusions Eltoprazine inhibits the sensitization of striatonigral medium‐sized GABA spiny neurons (the direct pathway) to l ‐dopa and their overactivation associated with dyskinesias appearance. Activation of 5‐HT 1A and 5‐HT 1B receptors regulating striatal glutamate transmission, but not striatal ectopic dopamine release, might underlie the symptomatic effect of eltoprazine. © 2015 International Parkinson and Movement Disorder Society