5-Hydroxytryptamine 1a (5-HT 1a ) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopainduced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT 1a receptors and also possess dopamine antagonist actions. We now report on the effects of (2R), a selective 5-HT 1a agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(ϩ)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(ϩ)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(ϩ)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(ϩ)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT 1a recep-(1.0 mg/kg s.c.). Administration of (R)-(ϩ)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D 2 /D 3 dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT 1a agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

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Reduced expression of dyskinesia is observed in levodopa-primed MPTP-treated common marmosets when dopamine agonists are used to replace levodopa. We now investigate whether a combination of the D-2/D-3 agonist pramipexole and levodopa also reduces dyskinesia intensity while maintaining the reversal of motor disability. Drug naïve, non-dyskinetic MPTP-treated common marmosets were treated daily for up to 62 days with levodopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) or pramipexole (0.04-0.3 mg/kg BID) producing equivalent reversal of motor disability and increases in locomotor activity. Levodopa alone resulted in marked dyskinesia induction but little or no dyskinesia resulted from the administration of pramipexole. From day 36, some animals were treated with a combination of levodopa (3.125-6.25 mg/kg plus carbidopa 12.5 mg/kg p.o. BID) and pramipexole (0.1-0.2 mg/kg p.o. SID). This improved motor disability to a greater extent than occurred with levodopa alone. Importantly, while dyskinesia was greater than that produced by pramipexole alone, the combination resulted in less intense dyskinesia than produced by levodopa alone. These results suggest that pramipexole could be administered with a reduced dose of levodopa to minimize dyskinesia in Parkinson's disease while maintaining therapeutic efficacy.

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