Nicotine-mediated improvement in l-dopa-induced dyskinesias in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function

l-Dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term l-dopa therapy for Parkinson's disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using l-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 μg/ml via drinking water) prevented the development of LIDs by ~ 75%. This improvement was maintained when the nicotine dose was lowered to 50 μg/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine's ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and 3H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K+, α4β2* and α6β2* nAChR-evoked 3H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson's disease.

► Nicotine pretreatment reduced LIDs in monkeys with moderate parkinsonism.
► The nicotine-mediated improvement in LIDs was dose dependent.
► Nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism.
► Nicotine-mediated improvement in LIDs is dependent on nerve terminal integrity.
► Nicotine may best reduce LIDs in patients with mild-moderate Parkinson's disease.