On-off effects of dopamine receptor agonists in the hemi-parkinsonian rat

Rats lesioned in one substantia nigra were treated daily with bromocriptine, SKF-77434 or cocaine and their rotational (circling) behavior was quantified. Within animal fluctuations in response to the direct-acting agonists were remarkable. In consecutive daily sessions individual animals completed from zero to hundreds or thousands of rotations. Every rat was totally unresponsive to drug treatment at least once in 14 days, with a response failure rate > or = 30% for both 1.0 mg/kg bromocriptine and 0.25 mg/kg SKF-77434. When the bromocriptine dose was increased from 1 to 2.5 to 5 mg/kg the response stabilized in some animals, and overall failure rate declined. In the SKF-77434-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. Rats treated repeatedly with the indirect agonist cocaine exhibited no response failures indicating that failures in response to the direct agonists were unlikely to be due to procedural artifact. The results suggest the possibility that large changes in responsivity to direct dopamine receptor agonists are a characteristic of their interaction with the denervated striatum. This approach may prove useful for study of the on-off effects that typically develop in parkinsonism and for identification of drugs with lesser propensity to induce such effects.