The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Huot, Philippe; Johnston, Tom H.; Koprich, James B.; Fox, Susan H.; Brotchie, Jonathan M.

doi:10.1124/pr.111.005678

Cited by 293 publications

(252 citation statements)

References 601 publications

(565 reference statements)

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“…Dopamine depletion and chronic levodopa create an imbalance in striatal neurotransmitter systems and glutamatergic, serotonergic, and peptidergic system changes have been noted in LIDs 6. Previous findings in animal models also support direct involvement of the nicotinic cholinergic system.…”

Section: Introductionmentioning

confidence: 85%

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

Brumberg

Küsters

Al‐Momani

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo investigate the association between levodopa‐induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease.MethodsThis study included 13 Parkinson's disease patients with peak‐of‐dose levodopa‐induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5‐[123I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single‐photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane single‐photon emission computed tomography, to measure dopamine reuptake transporter density and 2‐[18F]fluoro‐2‐deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed.ResultsDensity of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side.InterpretationOur findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic‐depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.

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Section: Introductionmentioning

confidence: 85%

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

Brumberg

Küsters

Al‐Momani

et al. 2017

Ann Clin Transl Neurol

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“…The finding that nicotine and nAChR agonists improve LIDs with no apparent effect on parkinsonism is consistent with preclinical studies, suggesting that these two behaviors may be differentially regulated by the direct and indirect pathways. Activation of the direct pathway may be more closely associated with LIDs, whereas parkinsonism may be linked to activation of the indirect pathway (Santini et al, 2008;Kravitz et al, 2010;Huot et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Although L-DOPA is one of the most effective therapies for Parkinson's disease, its continued use leads to abnormal involuntary movements or dyskinesias that may severely affect the quality of life of Parkinson's disease patients (Cenci and Konradi, 2010;Brotchie and Jenner, 2011;Carta and Bezard, 2011;Fisone and Bezard, 2011;Iravani and Jenner, 2011;Prashanth et al, 2011;Rascol et al, 2011;Poewe et al, 2012;Huot et al, 2013). As there are few treatment options to manage L-DOPA-induced dyskinesias (LIDs), novel therapeutic approaches are critical.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Zhang

Mallela

Sohn

et al. 2013

J Pharmacol Exp Ther

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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-DOPAinduced 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 5 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 mg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective a4b2*/a6b2* nAChR agonist 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 5 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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“…These abnormal involuntary movements are a serious debilitating side effect of L-Dopa therapy, the gold standard of treatment of Parkinson's disease, and they develop in most patients with continued L-Dopa use (Obeso et al, 2010;Meissner et al, 2011;Schapira and Jenner, 2011;Wichmann et al, 2011;Iravani et al, 2012;Huot et al, 2013). Currently, the only drug approved for LIDs is amantadine, and it is of only limited effectiveness.…”

Section: Introductionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

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Previous studies in Parkinsonian rats and monkeys have shown that b2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce L-Dopa-induced dyskinesias (LIDs), a serious complication of L-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of a7 nAChRs in LIDs, we tested the effect of the potent, selective a7 agonist . MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the b2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo [3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, a7 and b2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either a7 or b2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease.

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The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Cited by 293 publications

References 601 publications

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

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