The monoamine re-uptake inhibitor UWA-101 improves motor fluctuations in the MPTP-lesioned common marmoset

PLoS One. 2012;7(9):e45587. doi: 10.1371/journal.pone.0045587. Epub 2012 Sep 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
  • Animals
  • Benzodioxoles / pharmacology*
  • Biogenic Monoamines / metabolism*
  • Callithrix
  • Dose-Response Relationship, Drug
  • Female
  • Levodopa / adverse effects
  • Methylamines / pharmacology*
  • Motor Activity / drug effects*
  • Movement Disorders / drug therapy
  • Movement Disorders / etiology
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Neurotransmitter Uptake Inhibitors / therapeutic use

Substances

  • Benzodioxoles
  • Biogenic Monoamines
  • Methylamines
  • N-methyl-1-cyclopropyl-1-piperonylmethylamine
  • Neurotransmitter Uptake Inhibitors
  • Levodopa
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine