Journal of Neural Transmission

, 117:55

The dopamine D2 receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with l-dopa

  • Michael John Jackson
  • Terrance H. Andree
  • Matthew Hansard
  • Diane C. Hoffman
  • Mark R. Hurtt
  • John H. Kehne
  • Thomas A. Pitler
  • Lance A. Smith
  • Gary Stack
  • Peter Jenner
Movement Disorders - Original Article

DOI: 10.1007/s00702-009-0323-9

Cite this article as:
Jackson, M.J., Andree, T.H., Hansard, M. et al. J Neural Transm (2010) 117: 55. doi:10.1007/s00702-009-0323-9

Abstract

Dopamine replacement therapy in Parkinson’s disease (PD) using l-dopa is invariably associated with a loss of drug efficacy (“wearing off”) and the onset of dyskinesia. The use of dopamine receptor partial agonists might improve therapeutic benefit without increased dyskinesia expression but may antagonise the effects of l-dopa. We now examine the effects of the novel high affinity, dopamine D2 receptor partial agonist, aplindore alone and in combination with l-dopa in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. In non-dyskinetic MPTP treated animals, aplindore (0.05–1.0 mg/kg p.o.) produced a dose-dependent reversal of motor disability and an increase in locomotor activity that was maximal at doses of 0.2 mg/kg and above. In animals previously exposed to l-dopa to induce dyskinesia, escalating and repeated dosing of aplindore (0.05–0.5 mg/kg p.o.) produced a sustained, dose-related improvement in motor disability and an increase in locomotor activity. The effects were maximal at a dose of 0.1 mg/kg and above and not different from those produced by l-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). Aplindore administration also led to dose-dependent expression of dyskinesia but at 0.1 mg/kg, this was significantly less intense than that produced by l-dopa. Administration of aplindore (1.0 mg/kg p.o.) in combination with l-dopa (2.5 mg/kg plus carbidopa 12.5 mg/kg p.o.) did not inhibit the reversal of motor deficits but improved motor disability and increased both locomotor activity and dyskinesia expression equivalent to that produced by l-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). These data suggest that dopamine receptor partial agonists would be effective in the treatment of Parkinson’s disease and would not inhibit the beneficial actions of l-dopa.

Keywords

Aplindore Partial agonist MPTP Primate Parkinson’s disease 

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Michael John Jackson
    • 1
  • Terrance H. Andree
    • 2
  • Matthew Hansard
    • 1
  • Diane C. Hoffman
    • 3
  • Mark R. Hurtt
    • 3
  • John H. Kehne
    • 3
  • Thomas A. Pitler
    • 3
  • Lance A. Smith
    • 1
  • Gary Stack
    • 2
  • Peter Jenner
    • 1
  1. 1.School of Health and Biomedical Sciences, Neurodegenerative Diseases Research CentreKing’s CollegeLondonUK
  2. 2.Discovery Neuroscience (THA) and Chemical and Screening Sciences (GS)Wyeth ResearchPrincetonUSA
  3. 3.Neurogen CorporationBranfordUSA