title: Eltoprazine prevents levodopa-induced dyskinesias by reducing striatal glutamate and direct pathway activity.
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 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-HT1A and 5-HT1B receptors regulating striatal glutamate transmission, but not striatal ectopic dopamine release, might underlie the symptomatic effect of eltoprazine.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.|Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Paolone
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.|Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Brugnoli
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.|Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Arcuri
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.|Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mercatelli
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.|Center for Neuroscience and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D010879:Piperazines; D017366:Serotonin Receptor Agonists; D018698:Glutamic Acid; D007980:Levodopa; C063828:eltoprazine; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D004298:Dopamine
keywords: Parkinson's disease; dyskinesia; levodopa; microdialysis