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 (3)H-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 (3)H-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.