VALIDATION OF A RODENT MODEL OF PARKINSONS-DISEASE - EVIDENCE OF A THERAPEUTIC WINDOW FOR ORAL SINEMET

Behavioral measures of parkinsonism that are more clinically relevant than rotometry have been developed for rats with severe unilateral dop amine depletions, and the validity of these measures is supported by r eports that these parkinsonian symptoms are attenuated by drugs that a re effective in the clinical setting. Although the therapeutic gold st andard, L-DOPA:carbidopa (Sinemet), effectively attenuates parkinsonia n symptoms, the beneficial effects of this drug are limited by the dys kinesias that it produces at higher doses. The range of effective dose s, from the minimum dose that produces beneficial effects to the dose that produces intolerable dyskinesias, is referred to as the ''therape utic window.'' It would be extremely valuable to assess, preclinically , the effects of novel treatments on the therapeutic window for Sineme t. The results of the present study support the validity of nondrug-in duced measures of parkinsonian symptoms in dopamine-depleted rats. Neu rological measures revealed large behavioral deficits in the affected forelimb analogous to the deficits exhibited in Parkinson's disease pa tients, and these deficits were significantly attenuated with some dos es of oral Sinemet (30-40 mg/kg). These drug effects on measures of pa rkinsonism were specific to performance with the affected limb. At sli ghtly higher doses (50 mg/kg), the rats were untestable due to severe dyskinesias. The results of the present study suggest that it is possi ble to investigate the therapeutic potential of novel treatments as we ll as their effects on the therapeutic window of oral Sinemet in this rodent model of Parkinson's disease.