Eltoprazine prevents levodopa‐induced dyskinesias by reducing striatal glutamate and direct pathway activity. Issue 13 (24th July 2015)

• Record Type: Journal Article
• Authors: Paolone, Giovanna; Brugnoli, Alberto; Arcuri, Ludovico; Mercatelli, Daniela; Morari, Michele
• Is Part Of: Movement disorders. Volume 30:Issue 13(2015)
• Page Start: 1728
• Page End: 1738
• Publication Date: 2015-07-24
• Subjects: dyskinesia -- levodopa -- microdialysis -- Parkinson's disease; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.26326
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: 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‐HT1A or 5‐HT1B receptor agonists, and, very recently, the mixed 5‐HT1A /5‐HT1B receptor agonist, eltoprazine, proved effective in inhibitingl ‐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 withl ‐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 inl ‐dopa‐primed dyskinetic rats acutely challenged withl ‐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 thel ‐dopa‐induced increase in striatal dopamine. Conclusions: Eltoprazine inhibits the sensitization of striatonigral medium‐sized GABA spiny neurons (the direct pathway) tol ‐dopa and their overactivation associated with dyskinesias appearance. Activation of 5‐HT1A and 5‐HT1B 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