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. 2013 Sep;28(10):1398-406.
doi: 10.1002/mds.25594. Epub 2013 Jul 8.

Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson's disease

Maryka Quik  1 , Archana Mallela, Jason Ly, Danhui Zhang
Affiliations

Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson's disease

Maryka Quik et al. Mov Disord. 2013 Sep.

Abstract

Although 3,4-dihydroxyphenylalanine (levodopa) is the gold-standard treatment for Parkinson's disease, it can lead to disabling dyskinesias. Previous work demonstrated that nicotine reduces levodopa-induced dyskinesias (LIDs) in several parkinsonian animal models. The goal of this study was to determine whether the duration of nicotine administration affects its ability to reduce LIDs in levodopa-primed and levodopa-naíve monkeys and also to test whether tolerance develops to the beneficial effects of nicotine. Monkeys were injected with MPTP (1.9-2.0 mg/kg subcutaneously) over 3 to 5 months until parkinsonism developed. Nicotine (300 μg/mL) was administered in drinking water (over 4-6 months) to levodopa-primed or levodopa-naíve monkeys, with levodopa/carbidopa (10/2.5 mg/kg) gavaged twice daily. One set of MPTP-lesioned monkeys (n = 23) was first gavaged with levodopa and subsequently received nicotine 4 weeks later, when dyskinesias plateaued, or 8 weeks later, when dyskinesias were established. A 60% to 70% decrease in LIDs was observed after several weeks of nicotine treatment in both groups. A second set of monkeys (n = 26) received nicotine 8 or 2 weeks before levodopa. In the 8-week nicotine pretreatment group, there was an immediate reduction in LIDs, which plateaued at 60% to 70%. In the 2-week nicotine pretreatment group, there were initial small decreases in LIDs, which plateaued at 60% to 70% several weeks later. Thus, nicotine pretreatment and nicotine post-treatment were similarly efficacious in reducing LIDs. The beneficial effect of nicotine persisted throughout the study (17-23 weeks). Nicotine did not worsen parkinsonism. These data suggest that nicotine treatment has potential as a successful antidyskinetic therapy for patients with Parkinson's disease.

Keywords: Parkinson's disease; dyskinesia; levodopa; nicotine; nicotinic; nonhuman primate.

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Conflict of interest statement

Relevant conflict of interest/financial disclosures: There are no conflicts of interest or disclosures.

Figures

FIG. 1
FIG. 1
Nicotine treatment reduces established LIDs when administered 4 wk (Group 1, top panels) or 8 wk (Group 2, bottom panels) after the start of L-dopa treatment. Values are the mean ± SEM of 5–6 monkeys. Significance of difference from vehicle, *P < 0.05, **P < 0.01, ***P < 0.001 using ANOVA followed by a Bonferroni post hoc test.
FIG. 2
FIG. 2
Nicotine treatment reduces LIDs when administered 8 wk (Group 3, top panels) or 2 wk (Group 4, bottom panels) before L-dopa. Values are the mean ± SEM of 4–8 monkeys. Significance of difference from vehicle, *P < 0.05, **P < 0.01 using ANOVA followed by a Bonferroni post hoc test.
FIG. 3
FIG. 3
Nicotine pre- and post-treatments similarly reduce the daily time course of LIDs. The panels show the effect of nicotine on LIDs at wk 15 or 16 of treatment (see timeline in Fig. 1). Values represent the median of 4–6 monkeys. Significance of difference from vehicle treatment, *P < 0.05, **P < 0.01 using a Mann-Whitney test.
FIG. 4
FIG. 4
The reduction in LIDs persists with continued nicotine treatment. Values represent the mean ± SEM of 5–6 monkeys. Significance of difference from vehicle, *P < 0.05, **P < 0.01, ***P < 0.001 using ANOVA followed by a Bonferroni post hoc test.
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