CGS-15873

Qualitative differences in pharmacological responsiveness to various types of dopamine agonists have been reported in rats that have undergone unilateral 6-hydroxydopamine (6-OHDA)-induced denervation of the nigro-striatal pathway. The present experiments further characterize these differences, pharmacologically and neurochemically. Rats were classified as having high rotational sensitivity (0.03 mg/kg SC apomorphine sufficient to induce more than 100 rotations/20 min) or low sensitivity (0.3 mg/kg SC apomorphine required to meet this criterion). High sensitivity rats showed marked contralateral rotational behavior (approximately 150 rotations/20 min) in response to apomorphine (ED50 = 0.08 mg/kg IP), CGS 15855A (ED50 = 0.07 mg/kg), CGS 15873A (ED50 = 0.43 mg/kg), (+)-3-PPP (ED50 = 2.3 mg/kg), (-)-3-PPP (ED50 = 0.87 mg/kg) and quinpirole (peak effective dose, 0.03 mg/kg). In low sensitivity rats, 3- to 10-fold higher doses of apomorphine induced a maximal rate of rotational behavior, but only partial effects were produced by quinpirole, CGS 15855A, CGS 15873A, (+)-3-PPP, and (-)-3-PPP (40-80 rotations/20 min). Because apomorphine is a nonselective D1 and D2 agonist, it is proposed that activation of either D1 or D2 receptors suffices to induce high rates of rotation in high sensitivity rats, whereas in low sensitivity rats, D1 or D2 agonism alone induces submaximal rotation rates. The ipsilateral rotational behavior induced by d-amphetamine was more pronounced and occurred at lower doses in the high-sensitivity rats. Striatal dopamine depletion on the lesioned side did not differ between the groups, but low sensitivity rats showed two-fold higher DOPAC/DA ratios on the lesioned side than did high-sensitivity rats.(ABSTRACT TRUNCATED AT 250 WORDS)