THE SIGNIFICANCE OF CONTINUOUS DOPAMINERGIC STIMULATION IN THE TREATMENT OF PARKINSONS-DISEASE

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease. No other drug marches its ability to suppress par kinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much b ecause of a decline in efficacy against core symptoms, but rather beca use of a rise in adverse effects. Most common are the motor response c omplications that appear within a few years of treatment initiation an d ultimately affect most parkinsonian patients. These progressively di sabling complications include response fluctuations and abnormal invol untary movements. Current evidence indicates that 'wearing-off' fluctu ations, typically the first motor complication to become clinically ev ident, initially reflect the loss of buffering normally provided by st riatal dopaminergic terminals. Thus, with increasing degeneration of t he nigrostriatal system, swings in plasma levodopa concentrations asso ciated with standard dosage regimens produce nonphysiological fluctuat ions in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sires downstream from the dop amine system and now appear to underlie the progressive worsening of ' wearing-off' phenomena as well as the eventual appearance of other res ponse complications.Chronic intermittent stimulation of normally tonic ally active dopaminergic receptors activates specific signalling casca des in striatal dopaminoceptive medium spiny neurons, and this evident ly results in long term potentiation of the synaptic efficacy of gluta mate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GAB Aergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, a ppear that medium spiny neuron function changes to favour the appearan ce of response fluctuations of the 'on-off' type and peak dose dyskine sias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contribu tes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian pati ents but also prevents their development in animal models of Parkinson 's disease. Thus, pharmaceutical approaches that provide relatively co ntinuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategi es are currently under development, and include various methods to pro long the duration of action of levodopa as well as the use of transder mally administered or very long acting dopamine agonists.