Wearing-off phenomenon that complicates levodopa therapy of Parkinson's disease 
has been attributed to a reduction in striatal dopamine storage due to the 
progressive degeneration of presynaptic dopaminergic terminals. To determine 
whether postsynaptic mechanisms also contribute to these response fluctuations, 
the duration of the antiparkinsonian response in parkinsonian patients grouped 
by disease severity was compared following discontinuation of a steady-state 
optimal-dose infusion of apomorphine. Although the plasma half-life of this 
dopamine receptor agonist remained constant, its mean efficacy half-time 
declined from 66 minutes in early, levodopa-naive patients to 33 minutes in 
advanced, complicated parkinsonians (p < 0.005). Since the motor effects of 
apomorphine do not depend on the presence of dopaminergic terminals, changes at 
the postsynaptic level undoubtedly contribute to the diminished response 
duration. The only slightly greater attenuation of levodopa's motor effects 
observed previously under similar conditions suggests these postjunctional 
alterations, possibly involving relatively plastic striatal dopaminoceptive 
systems, account for most of the shortening in the duration of levodopa action 
that underlie wearing-off fluctuations.