title: Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson's disease.
abstract: BACKGROUND
  The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior.
  
  
  OBJECTIVE
  We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.
  
  
  METHODS
  Rotational behavior and abnormal involuntary movements, or disability and l-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, respectively. Moreover, in the rodent striatum, induction of immediate-early gene zif-268, an index of long-term changes, was correlated with dyskinesia.
  
  
  RESULTS
  In 6-hydroxydopamine-lesioned rats, combined administration of l-dopa (4 mg/kg) plus eltoprazine (0.6 mg/kg) plus preladenant (0.3 mg/kg) significantly prevented or reduced dyskinetic-like behavior without impairing motor activity. Zif-268 was increased in the striatum of rats treated with l-dopa and l-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after chronic treatment in both the dyskinetic and l-dopa-non-primed groups. Moreover, acute l-dopa plus eltoprazine plus preladenant prevented worsening of motor performance (adjusting step) and sensorimotor integration deficit. Similar results were obtained in MPTP-treated monkeys, where a combination of preladenant with eltoprazine was found to counteract dyskinesia and maintain the full therapeutic effects of a low dose of l-dopa.
  
  
  CONCLUSIONS
  Our results suggest a promising nondopaminergic pharmacological strategy for the treatment of dyskinesia in PD. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pinna
authors.affiliation: Motac Neuroscience Ltd, Manchester, UK.|Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
authors.forename: Wai Kin D
authors.initials: WK
authors.lastname: Ko
authors.affiliation: Department of Biomedical Sciences, section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Costa
authors.affiliation: Department of Biomedical Sciences, section of Physiology, University of Cagliari, Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.affiliation: Department of Biomedical Sciences, section of Physiology, University of Cagliari, Cagliari, Italy.
authors.forename: Camino
authors.initials: C
authors.lastname: Fidalgo
authors.affiliation: Department of Biomedical Sciences, section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Simola
authors.affiliation: Motac Neuroscience Ltd, Manchester, UK.|Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.affiliation: Motac Neuroscience Ltd, Manchester, UK.|Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.|Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Department of Biomedical Sciences, section of Physiology, University of Cagliari, Cagliari, Italy.
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
authors.affiliation: National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.|Department of Biomedical Sciences, section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morelli
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000517:prevention & control; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000978:Antiparkinson Agents; D010879:Piperazines; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D007980:Levodopa; C063828:eltoprazine; C539997:2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine
keywords: adenosine A2A receptor antagonist; dyskinesia; non-human primate; rodent; serotonin 5-HT1A/1B receptor agonist