Dyskinesia, secondary to
dopamine replacement
therapy, is the major complication of currently available
therapies for
Parkinson's disease. Alpha(2)
adrenoceptor antagonists, such as
idazoxan, can significantly reduce
levodopa-induced
dyskinesia in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-lesioned, nonhuman primate model of
Parkinson's disease and in human. This action of
adrenoceptor antagonists may involve blockade of the actions of
noradrenaline synthesised from
levodopa. We hypothesise that, because
dopamine receptor agonists, such as
apomorphine, cannot be metabolised to produce
noradrenaline, activation of
adrenoceptors may not be involved in
dyskinesia produced by such agents. If this were the case,
idazoxan would not be expected to reduce
apomorphine-induced
dyskinesia.
MPTP-lesioned marmosets with stable
dyskinesia induced by prolonged
levodopa therapy were given an acute challenge with
apomorphine (0.3 mg/kg subcutaneously) or
levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose
dyskinesia.
Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either
apomorphine or
levodopa.
Idazoxan abolished
levodopa-induced
dyskinesia but did not affect
apomorphine-induced
dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test).
Idazoxan also extended the anti-parkinsonian actions of
levodopa but did not affect those of
apomorphine. The pharmacological characteristics of the neural mechanisms underlying
levodopa-induced
dyskinesia and
apomorphine-induced
dyskinesia in
parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2)
adrenoceptors. Specifically,
levodopa, but not
apomorphine-induced
dyskinesia, involves activation of
adrenoceptors. This finding may have major implications for understanding
dyskinesia and should be borne in mind when designing clinical studies in which
levodopa or
dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs.