Sensitization, response fluctuation and long-term effect of SKF-82958 and bromocriptine in the hemi-parkinsonian rat.

Rats with a unilateral 6-hydroxydopamine lesion of substantia nigra were treated with the dopamine agonists SKF-82958 (D1 receptor selective) or bromocriptine (D2 receptor-selective) and their circling response recorded. Both of the compounds induced an acute episode of rotation directed away from the lesioned side. Consecutive daily treatments with either compound usually resulted in a significantly increased average response (sensitization) over a 3- to 6-day treatment period. But nearly all animals treated with low doses of either SKF-82958 or bromocriptine exhibited one or more days when they were totally unresponsive to drug treatment. Response fluctuations thus were not exclusively associated with D1 or D2 receptor agonist treatment. When subsequently tested, undrugged, in the drug-associated environment, 2, 4 and 10 weeks after their last drug treatment, rats that had previously been treated with SKF-82958 exhibited rapid contralateral rotation while rats that had previously been treated with bromocriptine showed no such undrugged rotation. This result is consistent with previous findings that the D1 receptor agonist, SKF-38393, but not the D2 receptor agonist, quinpirole, had long-term behavioral effect in nigral rats, and suggests that persistent motor consequences of limited treatment with dopamine receptor agonists are D1 receptor-related.