DOPAMINERGIC SYSTEMS AND PARKINSONS-DISEASE - SOME LATEST DEVELOPMENTS IN PATHOGENETIC, DIAGNOSTIC AND PHARMACOTHERAPEUTIC INVESTIGATIONS

Patients suffering from Parkinson's disease (PD) display severe and pr ogressive deficits in motor behavior, predominantly as a consequence o f the degeneration of dopaminergic neurons, located in the mesencephal on and projecting to striatal regions. The cause of PD is still an eni gma. In general, pharmacotherapy comprises symptomatic treatment with dopaminergic compounds, which induce a dramatic initial improvement, a lthough serious problems gradually develop after longterm treatment. T his paper describes some recent investigations in pathogenetic, diagno stic and pharmacotherapeutic mechanisms related to dopaminergic system s and PD, as they have been performed in our group. Pathogenetic mecha nisms will be highlighted along the line of the oxidative stress hypot hesis and especially the role of glutathione will be discussed in this respect. Strong indications exist that a decrease in mesencephalic gl utathione precedes the dopamine depletion in this brain region of PD p atients. By using iodinated radioligands, selective for dopamine trans porters, it is possible now to visualize the degeneration of the dopam inergic neurons with SPECT in the living patient. This creates the pos sibility to follow the degeneration rate of the dopaminergic neurons a nd to monitor eventually therapeutic effects of neuroprotective agents in longitudinal studies. Sofar, the dopaminergic drugs used for the p harmacotherapy of PD have mainly been confined to L-DOPA and D-2 recep tor agonists. It will be demonstrated, especially from studies perform ed in MPTP-lesioned monkeys, that some recently developed D-1 receptor agonists are able to induce dramatic improvements in this animal mode l.