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.