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@article{e6385b61e558499aa9ee241af98d95da,
title = "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.",
keywords = "5-HT1A RECEPTOR AGONIST, STRIATAL DOPAMINE RELEASE, PARKINSONS-DISEASE, RAT STRIATUM, IN-VIVO, 8-OH-DPAT, SARIZOTAN, BRAIN, ANTAGONISTS, EXPRESSION",
author = "Iravani, {Mahmoud M.} and Kayhan Tayarani-Binazir and Chu, {Wing B.} and Jackson, {Michael J.} and Peter Jenner",
year = "2006",
month = dec,
doi = "10.1124/jpet.106.110429",
language = "English",
volume = "319",
pages = "1225--1234",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

RIS

TY - JOUR

T1 - 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

AU - Iravani, Mahmoud M.

AU - Tayarani-Binazir, Kayhan

AU - Chu, Wing B.

AU - Jackson, Michael J.

AU - Jenner, Peter

PY - 2006/12

Y1 - 2006/12

N2 - 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.

AB - 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.

KW - 5-HT1A RECEPTOR AGONIST

KW - STRIATAL DOPAMINE RELEASE

KW - PARKINSONS-DISEASE

KW - RAT STRIATUM

KW - IN-VIVO

KW - 8-OH-DPAT

KW - SARIZOTAN

KW - BRAIN

KW - ANTAGONISTS

KW - EXPRESSION

U2 - 10.1124/jpet.106.110429

DO - 10.1124/jpet.106.110429

M3 - Article

VL - 319

SP - 1225

EP - 1234

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -