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. 2013 Oct;347(1):225-34.
doi: 10.1124/jpet.113.207639. Epub 2013 Jul 31.

Nicotinic receptor agonists reduce L-DOPA-induced dyskinesias in a monkey model of Parkinson's disease

Danhui Zhang  1 , Archana Mallela, David Sohn, F Ivy Carroll, Merouane Bencherif, Sharon Letchworth, Maryka Quik
Affiliations

Nicotinic receptor agonists reduce L-DOPA-induced dyskinesias in a monkey model of Parkinson's disease

Danhui Zhang et al. J Pharmacol Exp Ther. 2013 Oct.

Abstract

Abnormal involuntary movements or dyskinesias are a serious complication of long-term l-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases l-DOPA-induced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n = 23) were first administered l-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs ∼50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 µg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective α4β2*/α6β2* nAChR agonist TC-8831 [3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n = 16) that were nAChR drug-naïve. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in l-DOPA-treated Parkinson's disease patients.

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Figures

Fig. 1.
Fig. 1.
Varenicline treatment reduces LIDs. MPTP-lesioned monkeys were gavaged with l-DOPA twice daily, 5 days per week. Varenicline was given orally twice daily at a 3.5-hour interval at the same time as l-DOPA. The timeline is depicted in the upper panel. The middle panel shows the total dyskinesia scores (expressed as % vehicle) averaged over 2–3 days during the 4-hour period following the afternoon dose of l-DOPA (middle panel). For comparison, the lower panel illustrates the effect of nicotine (300 µg/ml in the drinking water) on LIDs for the same time period as the varenicline data. Values are the mean ± S.E.M. of 5–12 monkeys. Significance of difference of drug treatment from vehicle: ***P < 0.001 using two-way ANOVA followed by a Bonferroni post-hoc test.
Fig. 2.
Fig. 2.
Varenicline treatment decreases the hourly time course of LIDs. Monkeys were treated as described in the legend of Fig. 1. The data shown are for the afternoon 0.03 mg/kg varenicline dose averaged over several days. The effect of nicotine on LIDs is shown in the lower panel for comparison. The symbols depict the median of 5–12 monkeys. Significance of difference from vehicle using a Mann–Whitney test: ***P < 0.001.
Fig. 3.
Fig. 3.
TC-8831 treatment decreases LIDs. The effect of TC-8831 was tested in a set of MPTP-lesioned monkeys previously exposed to nicotine and nAChR drugs (set A), as well as in a set of nAChR drug–naïve MPTP-lesioned monkeys (set B). The monkeys were gavaged with l-DOPA twice daily, 5 days per week. TC-8831 (0.01–0.30 mg/kg) was given orally twice daily at a 3.5-hour interval at the same time as l-DOPA. The timeline is depicted in the upper panel. The middle panel shows the total dyskinesia scores (expressed as % vehicle) averaged over 2–3 days during the 4-hour period following the afternoon dose of l-DOPA. For comparison, the lower panel illustrates the effect of nicotine (300 µg/ml in the drinking water) on LIDs for the same time period as the TC-8831 data. Values are the mean ± S.E.M. of 5–6 monkeys. Significance of difference of drug treatment from vehicle: *P < 0.05; **P < 0.01; ***P < 0.001 using two-way ANOVA followed by a Bonferroni post-hoc test.
Fig. 4.
Fig. 4.
TC-8831 treatment decreases the hourly time course of LIDs. TC-8831 was tested in a set of MPTP-lesioned monkeys previously exposed to nicotine and nAChR drugs (set A), as well as in a set of nAChR drug–naïve MPTP-lesioned monkeys (set B). Drug treatments were as described in the legend of Fig. 3, with the data shown for the afternoon 0.10 mg/kg TC-8831 dose averaged over several days. The effect of nicotine on LIDs is shown in the lower panels for comparison. The symbols depict the median of 5–6 monkeys. Significance of difference from vehicle using a Mann–Whitney test: **P < 0.01; ***P < 0.001.
Fig. 5.
Fig. 5.
No tolerance to the TC-8831–mediated decline in LIDs with repeated dosing. TC-8831 administration was retested after a 2–3-week washout period in set A (nAChR drug primed) and set B (nAChR drug naïve). The monkeys were gavaged with l-DOPA twice daily, 5 days per week. TC-8831 (0.01–0.05 mg/kg) was given orally twice daily at a 3.5-hour interval at the same time as l-DOPA. The timeline is depicted in the upper panel. The middle panel shows the total dyskinesia scores (expressed as % vehicle) averaged over 2–3 days during the 4-hour period following the afternoon dose of l-DOPA. For comparison, the lower panel illustrates the effect of nicotine (300 µg/ml in the drinking water) on LIDs for the same time period as the TC-8831 data. Values are the mean ± S.E.M. of 5–6 monkeys. Significance of difference of drug treatment from vehicle: *P < 0.05; **P < 0.01; ***P < 0.001 using two-way ANOVA followed by a Bonferroni post-hoc test.
Fig. 6.
Fig. 6.
Hourly time course showing no tolerance to the TC-8831–mediated decline in LIDs with continued dosing. TC-8831 was retested in a set of MPTP-lesioned monkeys previously exposed to nicotine and nAChR drugs (set A), as well as in a set of nAChR drug–naïve MPTP-lesioned monkeys (set B). Drug treatments were as described in the legend of Fig. 5, with the data shown for the afternoon 0.03 mg/kg TC-8831 dose averaged over several days. The effect of nicotine on LIDs is shown in the lower panels for comparison. The symbol depicts the median of 5–6 monkeys. Significance of difference from vehicle using a Mann–Whitney test: **P < 0.01; ***P < 0.001.
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