Behavioral measures of
parkinsonism that are more clinically relevant than rotometry have been developed for rats with severe unilateral
dopamine depletions, and the validity of these measures is supported by reports that these parkinsonian symptoms are attenuated by drugs that are effective in the clinical setting. Although the therapeutic gold standard,
L-DOPA:
carbidopa (
Sinemet), effectively attenuates parkinsonian symptoms, the beneficial effects of this
drug are limited by the
dyskinesias that it produces at higher doses. The range of effective doses, from the minimum dose that produces beneficial effects to the dose that produces intolerable
dyskinesias, is referred to as the "therapeutic window." It would be extremely valuable to assess, preclinically, the effects of novel treatments on the therapeutic window for
Sinemet. The results of the present study support the validity of nondrug-induced measures of parkinsonian symptoms in
dopamine-depleted rats. Neurological measures revealed large behavioral deficits in the affected forelimb analogous to the deficits exhibited in
Parkinson's disease patients, and these deficits were significantly attenuated with some doses of oral
Sinemet (30-40 mg/kg). These
drug effects on measures of
parkinsonism were specific to performance with the affected limb. At slightly higher doses (50 mg/ kg), the rats were untestable due to severe
dyskinesias. The results of the present study suggest that it is possible to investigate the therapeutic potential of novel treatments as well as their effects on the therapeutic window of oral
Sinemet in this rodent model of
Parkinson's disease.