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 withIncreased Motor Disability

摘要

5-Hydroxytryptamine 1a (5-HT_(1a)) receptor agonists,such as sarizotan and tandospirone,are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropy-ridine (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)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT],a selective 5-HT_(1a) agonist lacking dopaminergic activity,on motor disability and dyskinesia (chorea and dysto-nia) 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-HT_(1a) 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-HT_(1a) agonists do not provide an effective means of suppressing levodopa-induced dyskinesia,except with worsening of parkinsonism.