MOTOR RESPONSE COMPLICATIONS AND THE FUNCTION OF STRIATAL EFFERENT SYSTEMS

Motor response complications eventually appear in most patients with a dvanced Parkinson's disease being treated with levodopa. The interval between onset of parkinsonism and emergence of these adverse events ap pears independent of the dose or the duration of therapy. Current evid ence suggests that ''wearing-off'' fluctuations largely reflect the lo ss of normally functioning dopaminergic terminals, although postsynapt ic alterations contribute somewhat to the underlying decline in the du ration of levodopa's antiparkinsonian action. ''On-off'' fluctuations and peak-dose dyskinesias, on the other hand, appear to arise mainly a s a consequence of postjunctional alterations that follow exposure to nonphysiologic intrasynaptic dopamine fluctuations in patients who hav e lost the buffering afforded by dopaminergic terminals. Studies in ra ts with B-hydroxydopamine lesions indicate that striking functional al terations occur in striatal dopaminoceptive systems as a result of dop aminergic denervation and that levodopa replacement, particularly when given intermittently, fails to normalize these changes. To the extent that similar alterations contribute to the appearance of motor compli cations, the successful symptomatic therapy of Parkinson's disease may require continuous dopaminergic stimulation, as well as direct pharma cologic targeting of striatal dopaminoceptive systems.