D1 dopamine receptor activity of anti-parkinsonian drugs.

Abstract Clinical and preclinical investigations suggest that stimulation of D 1 dopamine receptors may be responsible for dyskinesias induced by dopamine agonist treatment of Parkinson's Disease (PD), and that these dyskinesias may be decreased by treatment with a D 1 antagonist (clozapine). Therefore, the effects of dopamine agonists and antagonists have been investigated in a primary cerebellar granule cell model of cAMP formation mat seems to be highly responsive to the D 1 receptors. SKF 38393, lisuride, apomorphine, pergolide, dopamine, bromocriptine and 7-OH-DPAT showed concentration-dependent increases in cAMP formation, with EC 50 s (in μM) of 0.013, 0.053, 0.25, 1.04, 2.18, 50.9 and 54.4, respectively. SKF 38393, apomorphine, dopamine and pergolide had similar intrinsic activity (100%), while the intrinsic activities of 7-OH-DPAT, bromocriptine and lisuride were 28.0%, 20.7% and 17.2%, respectively. SCH 23390, a selective D 1 dopamine receptor antagonist, blocked an increase in cAMP formation produced by EC 50 concentrations of all of the dopamine agonists investigated in this study. Clozapine concentration-dependently blocked pergolide-induced increases in cAMP and was ∼1700-fold less potent than SCH 23390 (IC 50 : 0.97 μM and 0.56 nM, respectively). U-95666A (1–1000 μM), selective for the D 2 receptors, showed no significant effect on cAMP, while pramipexole (0.1 -100 μM), a D 3 preferring agonist, did not elevate cAMP. These data suggest that primary cerebellar granule cell cultures are an excellent model for measuring D 1 dopamine receptor-mediated changes in cellular cAMP. The results are discussed with reference to the relationship between the D 1 receptor-stimulated increase in cAMP formation and the induction of dyskinesia in humans by these anti-parkinsonian drugs.