title: Dyskinesias in normal squirrel monkeys induced by nomifensine and levodopa.
abstract: The mechanisms underlying levodopa-induced dyskinesias are unclear. They might involve impairment of the buffering capacity for dopamine, resulting from loss of nigral dopaminergic cells and the subsequent degeneration of their terminals in striatum. This study investigated the role of striatal buffering in the development of dyskinesias. We used nomifensine, a selective dopamine reuptake blocker, to pharmacologically impair presynaptic buffering capacity in normal squirrel monkeys. Dyskinesias were assessed at 30-min intervals for 4 h after twice-daily treatment with drug. As previously reported by our group, animals receiving levodopa alone (15 mg/kg) exhibited dyskinetic behavior. Treatment with nomifensine alone (3 mg/kg) also induced dyskinesias. Furthermore, combining levodopa with nomifensine significantly increased dyskinesias. Over 4 weeks of treatment, the animals developed tolerance to the dyskinesia-inducing effect of nomifensine. The development of tolerance was prevented by concurrent treatment with levodopa. These results show that impairing buffering by preventing dopamine reuptake can induce dyskinesias and can also augment levodopa-induced dyskinesias. Thus, this study suggests that diminished buffering capacity for dopamine could play a role in the development of dyskinesias, and that an endogenous mechanism might exist that ameliorates dyskinesias.
authors.affiliation: The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. dtogasaki@att.net
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Togasaki
authors.forename: Peter
authors.initials: P
authors.lastname: Protell
authors.forename: Louis C S
authors.initials: LC
authors.lastname: Tan
authors.forename: J William
authors.initials: JW
authors.lastname: Langston
authors.forename: Donato A
authors.initials: DA
authors.lastname: Di Monte
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D004338:Drug Combinations; D004357:Drug Synergism; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D005260:Female; D007980:Levodopa / Q000633:toxicity*; D009627:Nomifensine / Q000633:toxicity*; D012453:Saimiri
chemical_list: D004338:Drug Combinations; D009627:Nomifensine; D007980:Levodopa