WEARING-OFF FLUCTUATIONS IN PARKINSONS-DISEASE - CONTRIBUTION OF POSTSYNAPTIC MECHANISMS

Wearing-off phenomenon that complicates levodopa therapy of Parkinson' s disease has been attributed to a reduction in striatal dopamine stor age due to the progressive degeneration of presynaptic dopaminergic te rminals. To determine whether postsynaptic mechanisms also contribute to these response fluctuations, the duration of the antiparkinsonian r esponse in parkinsonian patients grouped by disease severity was compa red following discontinuation of a steady-state optimal-dose infusion of apomorphine. Although the plasma half-life of this dopamine recepto r agonist remained constant, its mean efficacy half-time declined from 66 minutes in early, levodopa-naive patients to 33 minutes in advance d, complicated parkinsonians (p < 0.005). Since the motor effects of a pomorphine do not depend on the presence of dopaminergic terminals, ch anges at the postsynaptic level undoubtedly contribute to the diminish ed response duration. The only slightly greater attenuation of levodop a's motor effects observed previously under similar conditions suggest s these postjunctional alterations, possibly involving relatively plas tic striatal dopaminoceptive systems, account for most of the shorteni ng in the duration of levodopa action that underlie wearing-off fluctu ations.