In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\increased motor disability

Abstract

5-Hydroxytryptamine 1a (5-HT1a) 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-HT1a receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino) tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT1a agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(+)-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)-(+)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(+)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(+)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT1a receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]N-2-pyridinylcyclohexanecarboxamide maleate (WAY-100635) (1.0 mg/ kg s. c.). Administration of (R)-(+)-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-HT1a agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.