title: Nicotinic receptor agonists reduce L-DOPA-induced dyskinesias in a monkey model of Parkinson's disease.
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.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California (D.Z., A.M., D.S., M.Q.); Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.); and Targacept, Inc., Winston-Salem, North Carolina (M.B., S.L.).
authors.forename: Danhui
authors.initials: D
authors.lastname: Zhang
authors.forename: Archana
authors.initials: A
authors.lastname: Mallela
authors.forename: David
authors.initials: D
authors.lastname: Sohn
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Sharon
authors.initials: S
authors.lastname: Letchworth
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D009538:Nicotine / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000502:physiology; D012453:Saimiri
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D007980:Levodopa; D009538:Nicotine
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