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 D(2) 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.