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
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
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DOI：
10.1124/jpet.106.110429
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Jenner, Peter
中科院分区：
文献类型：
--
作者：
Iravani, Mahmoud M.;Tayarani-Binazir, Kayhan;Jenner, Peter
5-据报道，羟色胺1a（5-HT 1a）受体激动剂，如沙立佐坦和坦度螺酮，可减少1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）治疗的猕猴和帕金森病中左旋多巴诱导的运动障碍，而不会加重运动障碍。然而，这些化合物对5-HT 1a受体不是特异性的，并且还具有多巴胺拮抗剂作用。我们现在报告（2 R）-（+）-8-羟基-2-（二正丙基氨基）四氢萘[（R）-（+）-8-OHDPAT]（一种缺乏多巴胺能活性的选择性5-HT 1a激动剂）对左旋多巴引发的MPTP治疗的普通绒猴的运动障碍和运动障碍（舞蹈病和肌张力障碍）的影响。将（R）-（+）-8-OHDPAT（0.2、0.6和2.0 mg/ kg s.c.）与左旋多巴/卡比多巴（12.5 mg/ kg，各p.o.）对于左旋多巴致敏的动物，剂量依赖性地减少左旋多巴诱导的舞蹈病，但不影响张力障碍运动。然而，（R）-（+）-8-OHDPAT治疗也减少了运动活动和运动残疾的逆转。（R）-（+）-8-OHDPAT单独给药对运动行为无影响。5-HT 1a受体拮抗剂N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]N-2-吡啶基环己烷甲酰胺马来酸盐（WAY-100635）（1.0 mg/ kg s. c.）。施用（R）-（+）-8-OHDPAT（0.6 mg/ kg s. c.）也减少了通过给予D-2/D-3多巴胺受体激动剂普拉克索（0.06mg/ kg p.o.）给予左旋多巴的MPTP治疗的动物。然而，普拉克索引起的自发活动增加和运动残疾逆转也受到抑制。这些数据表明，选择性5-HT 1a激动剂不提供抑制左旋多巴诱导的运动障碍的有效手段，除了帕金森综合征的恶化。
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.