Antiparkinsonian effects of the novel D 3 /D 2 dopamine receptor agonist, S32504, in MPTP‐lesioned marmosets: Mediation by D 2 , not D 3 , dopamine receptors

L ‐dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D 3 /D 2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D 2 vs. D 3 receptors, an issue we addressed with the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)–lesioned nonhuman primate model of Parkinson's disease. In L ‐dopa–primed animals, S32504 (0.16–2.5 mg/kg p.o.) dose‐dependently enhanced locomotor activity. This action was abolished by the D 2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D 3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug‐naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D 3 /D 2 agonist S32504 may offer advantages over L ‐dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D 2 , not D 3 , receptors. © 2006 Movement Disorder Society