title: Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia.
abstract: The serotonin system has emerged as a potential target for anti-dyskinetic therapy in Parkinson's disease. In fact, serotonin neurons can convert L-DOPA into dopamine, and mediate its synaptic release. However, they lack a feedback control mechanism able to regulate synaptic dopamine levels, which leads to un-physiological stimulation of post-synaptic striatal dopamine receptors. Accordingly, drugs able to dampen the activity of serotonin neurons can suppress L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Here, we investigated the ability of the 5-HT1A/1B receptor agonist anpirtoline to counteract L-DOPA-induced dyskinesia in L-DOPA-primed 6-OHDA-lesioned rats and MPTP-treated macaques. Results suggest that anpirtoline dose-dependently reduced dyskinesia both in rats and monkeys; however, the effect in MPTP-treated macaques was accompanied by a worsening of the Parkinson's disease score at significantly effective doses (1.5 and 2.0mg/kg). At a lower dose (0.75mg/kg), anpirtoline markedly reduced dyskinesia in 4 out of 5 subjects, but statistical significance was prevented by the presence of a non-responsive subject. These results provide further evidence that the serotonin neurons contribute both to the pro-dyskinetic effect of L-DOPA and to its therapeutic efficacy in the rat and monkey models of Parkinson's disease.
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bézard
authors.forename: Ana
authors.initials: A
authors.lastname: Muñoz
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.forename: Elsa Y
authors.initials: EY
authors.lastname: Pioli
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Gregory
authors.initials: G
authors.lastname: Porras
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010880:Piperidines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*
chemical_list: D000978:Antiparkinson Agents; D010880:Piperidines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; C075631:anpirtoline; D007980:Levodopa
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 5-HT1A/1B agonists; 6-OHDA; 6-hydroxy-dopamine; AIMs; DA; Dyskinesia; L-DOPA; L-DOPA-induced dyskinesia; LID; MPTP; PD; Parkinson's disease; Serotonin; TH; abnormal involuntary movements; dopamine; tyrosine hydroxylase