(1) Wearing-off phenomena, generally the initial motor complication in levodopa-treated Parkinsonian patients, have been attributed solely to the loss of dopamine (DA) storage capacity as a consequence of dopaminergic neuron degeneration. However, recent preclinical studies cast doubt on this view, since the duration of the motor effects of a single levodopa dose in rats rendered Parkinsonian by a fixed DA system lesion decrease during the course of daily levodopa therapy. Preliminary observations in Parkinsonian patients treated with the direct DA agonist, apomorphine, further support the view that post-junctional alterations resulting from intermittent levodopa treatment contribute substantially to the pathogenesis of wearing-off fluctuations. These changes appear relatively plastic, since a continuous infusion of levodopa for 10 days prolongs levodopa's duration of action by 30% and a 3~month infusion of lisuride, a DA agonist, does so by over 90%. (2) Evidence in support of presynaptic mechanisms operating to compensate for the loss of DA neurons in Parkinsonian patients derives from clinical studies showing the interval between the injection of levodopa and its peak antiparkinsonian response declines as disease severity advances. No change in this interval occurs with apomorphine which acts by directly stimulating postsynaptic receptors. Preliminary observations now suggest that a COMT inhibitor may substantially prolong the antiparkinsonian action of levodopa without increasing adverse effects associated with hyperdopaminergic stimulation. (3) Extrapyramidal motor function appears potently regulated by glutamatergic mechanisms. Intermittent levodopa administration to Parkinsonian rats, upregulates D2 DA receptor-mediated functions and down-regulates those mediated by D1 receptors. Resultant funneling of striatal output through the D2 pathway could contribute to the pathogenesis of motor complications. Acutely administered MK~801, a selective NMDA antagonist, normalizes the functional changes in both the D1 and D2 systems; drugs that block AMPA glutamate receptors do not have this effect. Indeed, AMPA and NMDA antagonists exert opposite effects on catalepsy induced by dopaminergic antagonists. (4) The hypothesis that glutamate replacement might confer symptomatic benefit to Alzheimer's disease patients whose cortical glutamatergic projections have degenerated, was evaluated by administration of cycloserine. This partial indirect NMDA agonist had no consistent effect on cognitive function.
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