ON-OFF EFFECTS OF DOPAMINE-RECEPTOR AGONISTS IN THE HEMI-PARKINSONIANRAT

Rats lesioned in one substantia nigra were treated daily with bromocri ptine, SKE-77434 or cocaine and their rotational (circling) behavior w as quantified. Within animal fluctuations in response to the direct-ac ting agonists were remarkable. In consecutive daily sessions individua l animals completed from zero to hundreds or thousands of rotations. E very rat was totally unresponsive to drug treatment at least once in 1 4 days, with a response failure rate greater-than-or-equal-to 30% for both 1.0 mg/kg bromocriptine and 0.25 mg/kg SKF-77434. When the bromoc riptine dose was increased from 1 to 2.5 to 5 mg/kg the response stabi lized in some animals, and overall failure rate declined. In the SKF-7 7434-treated rats the interval between administrations was manipulated . The response failure rate did not decrease when drug was given every third day, but decreased significantly upon weekly administration. Ra ts treated repeatedly with the indirect agonist cocaine exhibited no r esponse failures indicating that failures in response to the direct ag onists were unlikely to be due to procedural artifact. The results sug gest the possibility that large changes in responsivity to direct dopa mine receptor agonists are a characteristic of their interaction with the denervated striatum. This approach may prove useful for study of t he on-off effects that typically develop in parkinsonism and for ident ification of drugs with lesser propensity to induce such effects.