Treatment of
Parkinson's disease with
L-dopa is plagued in a majority of patients by
dyskinesias.
Noradrenaline/
dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist,
idazoxan, in a primate model of
Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to
L-dopa but had developed
dyskinesias which were manifested with each dose. In the first part of the study, seven doses of
idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of
L-dopa/
benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of
idazoxan (7.5 mg/kg) was administered daily for 10 days and
L-dopa was added to
idazoxan on days 1, 4, 7 and 10. Vehicle (empty
capsule) was used as control.
Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no
dyskinesias in three animals. In combination with
L-dopa,
idazoxan did not impair the antiparkinsonian response but significantly reduced
dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without
dyskinesias was prolonged. The antidyskinetic effect of
idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to
L-dopa was significantly potentiated by chronic administration of
idazoxan. Our results indicate that
idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to
L-dopa as it can reduce
dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.