Selective blockade of D3 dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate

To date, the lack of highly selective antagonists at the dopamine D3 receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson''s disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D3 versus D2 receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D3-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D3 receptor stimulation. Indeed, stimulation of D3 receptors may be detrimental to the anti-parkinsonian properties of D2/D3 agonists. Selectivity for stimulation of D2, over D3, receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson''s disease patients with established dyskinesia. [Copyright &y& Elsevier]