title: The monoamine re-uptake inhibitor UWA-101 improves motor fluctuations in the MPTP-lesioned common marmoset.
abstract: BACKGROUND
  The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson's disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of "good quality" ON-time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP-lesioned common marmoset.
  
  
  METHODS
  Marmosets were rendered parkinsonian by MPTP injection and "primed" by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle.
  
  
  RESULTS
  In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all P<0.05). UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia (by 62%, P<0.01). UWA-101 did not exacerbate the severity of dyskinesia (P>0.05). However, at the highest doses (6 and 10 mg/kg), UWA-101 increased the severity of psychosis-like behaviours (P<0.05).
  
  
  CONCLUSIONS
  Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gandy
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Reyes
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Piggott
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008744:Methylamines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D052117:Benzodioxoles; D015306:Biogenic Monoamines; D008744:Methylamines; C579241:N-methyl-1-cyclopropyl-1-piperonylmethylamine; D014179:Neurotransmitter Uptake Inhibitors; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine