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-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-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)-(+)-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 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-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.

• Authors: Mahmoud M Iravani, Kayhan Tayarani-Binazir, Wing B Chu, Michael J Jackson, Peter Jenner
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 319 Issue 3 Pg. 1225-34 (Dec 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16959959 (Publication Type: Journal Article)

Chemical References

• Benzothiazoles
• Dopamine Agents
• Dopamine Agonists
• Piperazines
• Pyridines
• Receptors, Dopamine D2
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Receptor, Serotonin, 5-HT1A
• Levodopa
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Pramipexole
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (pharmacology)
• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Benzothiazoles (pharmacology)
• Callithrix
• Data Interpretation, Statistical
• Dopamine Agents (toxicity)
• Dopamine Agonists (pharmacology)
• Dyskinesia, Drug-Induced (prevention & control)
• Female
• Levodopa (antagonists & inhibitors, toxicity)
• Male
• Motor Activity (drug effects)
• Piperazines (pharmacology)
• Pramipexole
• Pyridines (pharmacology)
• Receptor, Serotonin, 5-HT1A (drug effects)
• Receptors, Dopamine D2 (agonists)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)