1. Anti-tremor activity of talipexole produced by selective dopamine D2 receptor stimulation in cynomolgus monkeys with unilateral lesions in the ventromedial tegmentum
- Author
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Koichi Kitahara, Yasuko Kohno, Takeshi Koja, and Koichiro Fukuzaki
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Tegmentum Mesencephali ,medicine.drug_class ,Injections, Subcutaneous ,Dopamine Agents ,Administration, Oral ,Levodopa ,chemistry.chemical_compound ,Internal medicine ,Dopamine receptor D2 ,Tremor ,medicine ,Animals ,Hypnotics and Sedatives ,Bromocriptine ,Pharmacology ,SCH-23390 ,Behavior, Animal ,Receptors, Dopamine D2 ,Chemistry ,Azepines ,Talipexole ,Yohimbine ,Dopamine D2 Receptor Antagonists ,Macaca fascicularis ,Endocrinology ,Dopamine receptor ,Dopamine Agonists ,Sulpiride ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.
- Published
- 1997